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1.
J Am Soc Nephrol ; 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33853887

RESUMO

BACKGROUND: APOL1 variants contribute to the markedly higher incidence of ESKD in Blacks compared with Whites. Genetic testing for these variants in patients with African ancestry who have nephropathy is uncommon, and no specific treatment or management protocol for APOL1-associated nephropathy currently exists. METHODS: A multidisciplinary, racially diverse group of 14 experts and patient advocates participated in a Delphi consensus process to establish practical guidance for clinicians caring for patients who may have APOL1-associated nephropathy. Consensus group members took part in three anonymous voting rounds to develop consensus statements relating to the following: (1) counseling, genotyping, and diagnosis; (2) disease awareness and education; and (3) a vision for management of APOL1-associated nephropathy in a future when treatment is available. A systematic literature search of the MEDLINE and Embase databases was conducted to identify relevant evidence published from January 1, 2009 to July 14, 2020. RESULTS: The consensus group agreed on 55 consensus statements covering such topics as demographic and clinical factors that suggest a patient has APOL1-associated nephropathy, as well as key considerations for counseling, testing, and diagnosis in current clinical practice. They achieved consensus on the need to increase awareness among key stakeholders of racial health disparities in kidney disease and of APOL1-associated nephropathy and on features of a successful education program to raise awareness among the patient community. The group also highlighted the unmet need for a specific treatment and agreed on best practice for management of these patients should a treatment become available. CONCLUSIONS: A multidisciplinary group of experts and patient advocates defined consensus-based guidance on the care of patients who may have APOL1-associated nephropathy.

2.
Kidney Int ; 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33794228

RESUMO

APOL1 kidney risk variants (RVs) were identified in 2010 as major drivers of glomerular, tubulointerstitial, and renal microvascular disease in individuals with sub-Saharan African ancestry. In December 2020, the "APOL1 at Ten" conference summarized the first decade of progress and discussed controversies and uncertainties that remain to be addressed. Topics included trypanosome infection and its role in the evolution of APOL1 kidney RVs, clinical phenotypes in APOL1-associated nephropathy, relationships between APOL1 RVs and background haplotypes on cell injury and molecular mechanisms initiating disease, the role of clinical APOL1 genotyping, and development of novel therapies for kidney disease. Future goals were defined, including improved characterization of various APOL1 RV phenotypes in patients and experimental preclinical models; further dissection of APOL1-mediated pathways to cellular injury and dysfunction in kidney (and other) cells; clarification of gene-gene and gene-environment interactions; and evaluation of the role for existing and novel therapies.

4.
Am J Manag Care ; 26(11): 468-474, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33196280

RESUMO

OBJECTIVES: Optimizing care for patients with advanced kidney disease requires close collaboration between primary care physicians (PCPs) and nephrologists. Factors associated with PCP referral to nephrology were assessed in patients with estimated glomerular filtration rates (eGFRs) less than 30 mL/min/1.73 m2. STUDY DESIGN: Electronic health record review at an integrated health care network. METHODS: Factors associated with referral status were identified using Fisher's exact tests, t tests, and multivariable logistic regression. RESULTS: Of 133,913 patients regularly seeing PCPs between October 2017 and September 2019, 1119 had a final eGFR less than 30 mL/min/1.73 m2 and were not on renal replacement therapy. Care was provided by 185 PCPs (61 practices). Analyses were restricted to the 97.1% (n = 1087) of patients who were African American or European American. Of these, 54.6% had not been referred to nephrology. Nonreferred patients had higher numbers of PCP visits (P = .004). In contrast, referred patients were younger, were more often African American, and had PCPs at the academic medical center (all P < .0001). Referred patients had more complex medical histories with higher Charlson Comorbidity Index scores, more hospitalizations, and greater numbers of inpatient days (all P < .0001). Analyses restricted to patients with serum creatinine concentration of at least 2 mg/dL yielded similar results. Age, number of hospitalizations, ancestry, academic physician, diabetic end-organ damage, peripheral vascular disease, and tumor status were independent predictors of nephrology referral. CONCLUSIONS: Impediments to appropriately timed nephrology referrals persist in patients with high likelihoods of progression to end-stage kidney disease. Improved access to nephrology care should be rapidly addressed to meet targets in the 2019 Executive Order on Advancing American Kidney Health.

5.
Hypertension ; 76(6): 1717-1724, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33100049

RESUMO

Intensive blood pressure control decreases the rate of cardiovascular events by >25% compared with standard blood pressure control. We sought to determine whether the decrease in cardiovascular events seen with intensive blood pressure control is associated with an increased rate of other causes of hospitalization. This is a post hoc analysis of SPRINT (Systolic Blood Pressure Intervention Trial) in 9361 adult participants with hypertension and elevated cardiovascular risk. Participants were randomly assigned to an intensive or standard systolic blood pressure goal (<120 or <140 mm Hg, respectively). The primary outcome was hospitalization rates per 100 person-years for hospitalizations not associated with SPRINT primary events. After excluding hospitalizations linked to SPRINT primary events, there were 4678 participants with a rate of 19.70 hospitalizations per 100 person-years, compared with 4683 participants with a rate of 19.65 (P=0.37). Equivalence testing shows that these hospitalization rates were statistically equivalent at the P=0.05 level. Of those with hospitalizations, >1 hospitalization was seen in 38.8% of intensive arm participants and 41.9% of standard arm participants (P=0.08). The mean cumulative count of nonprimary event hospitalizations was comparable between the two arms. The most common causes of hospitalization were cardiovascular (23.6%) followed by injuries, including bone and joint therapeutic procedures (15.7%), infections (12.0%), and nervous systems disorders (10.7%). No categories of hospitalization were statistically more common in the intensive arm compared with the standard arm. Thus, the decrease in cardiovascular events seen with intensive blood pressure control is not associated with an increased rate of other causes of hospitalization. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

6.
Am J Nephrol ; 51(10): 797-805, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32906135

RESUMO

BACKGROUND: Kidney tubular atrophy on biopsy is a strong predictor of chronic kidney disease (CKD) progression, but tubular health is poorly quantified by traditional measures including estimated glomerular filtration rate (eGFR) and albuminuria. We hypothesized that urinary biomarkers of impaired tubule function would be associated with faster eGFR declines in persons with CKD. METHODS: We measured baseline urine concentrations of uromodulin, ß2-microglobulin (ß2m), and α1-microglobulin (α1m) among 2,428 participants of the Systolic Blood Pressure Intervention Trial with an eGFR <60 mL/min/1.73 m2. We used linear mixed models to evaluate biomarker associations with annualized relative change in eGFR, stratified by randomization arm. RESULTS: At baseline, the mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m2. In the standard blood pressure treatment arm, each 2-fold higher urinary uromodulin was associated with slower % annual eGFR decline (0.34 [95% CI: 0.08, 0.60]), whereas higher urinary ß2m was associated with faster % annual eGFR decline (-0.10 [95% CI: -0.18, -0.02]) in multivariable-adjusted models including baseline eGFR and albuminuria. Associations were weaker and did not reach statistical significance in the intensive blood pressure treatment arm for either uromodulin (0.11 [-0.13, 0.35], p value for interaction by treatment arm = 0.045) or ß2m (-0.01 [-0.08, 0.08], p value for interaction = 0.001). Urinary α1m was not independently associated with eGFR decline in the standard (0.01 [-0.22, 0.23]) or intensive (0.03 [-0.20, 0.25]) arm. CONCLUSIONS: Among trial participants with hypertension and CKD, baseline measures of tubular function were associated with subsequent declines in kidney function, although these associations were diminished by intensive blood pressure control.

7.
Perit Dial Int ; : 896860820953712, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32909931

RESUMO

This study evaluated intradialytic cerebral hemodynamics measured by transcranial Doppler (TCD) in intermittent hemodialysis (iHD) versus nightly peritoneal dialysis (NIPD). Intradialytic TCD was serially performed in chronic dialysis patients receiving iHD (n = 10) and NIPD (n = 10). A linear mixed model was used to model mean flow velocity (MFV), pulsatility index (PI), and mean arterial pressure (MAP) as functions of time and treatment group. Intradialytic cerebral volatility (IDCV) was calculated using the coefficient of variation (CV) and mean absolute value of change (AVC) of each patient's MFV, PI, and MAP values over time. Mixed model analyses found no significant difference between MFV, PI, and MAP treatment groups in change over time, though volatility differed significantly. Mean CV values for MFV, PI, and MAP were higher in iHD than NIPD (MFV 0.22 vs. 0.10, p = 0.005; PI 0.14 vs. 0.08, p = 0.003; MAP 0.057 vs. 0.032, p = 0.009). AVC values were similarly higher in iHD compared to NIPD (MFV 8.26 vs. 4.43, p = 0.04; PI 0.17 vs. 0.084, p < 0.001; MAP 6.05 vs. 2.9, p = 0.003). PI, MFV, and MAP were more stable in NIPD than iHD, as measured by intradialytic TCD monitoring. This study identifies IDCV as a unique TCD metric for intradialytic cerebral hemodynamics.

8.
Am J Nephrol ; 51(9): 695-704, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866949

RESUMO

BACKGROUND: Apolipoprotein L1 gene (APOL1) G1 and G2 kidney-risk variants (KRVs) cause CKD in African Americans, inducing mitochondrial dysfunction. Modifying factors are required, because a minority of individuals with APOL1 high-risk genotypes develop nephropathy. Given that APOL1 function is pH-sensitive and the pH of the kidney interstitium is <7, we hypothesized the acidic kidney interstitium may facilitate APOL1 KRV-induced mitochondrial dysfunction. METHODS: Human embryonic kidney (HEK293) cells conditionally expressing empty vector (EV), APOL1-reference G0, and G1 or G2 KRVs were incubated in media pH 6.8 or 7.4 for 4, 6, or 8 h. Genotype-specific pH effects on mitochondrial length (µm) were assessed using confocal microscopy in live cells and Fiji derivative of ImageJ software with MiNA plug-in. Lower mitochondrial length indicated fragmentation and early dysfunction. RESULTS: After 6 h doxycycline (Dox) induction in pH 6.8 media, G2-expressing cells had shorter mitochondria (6.54 ± 0.40) than cells expressing EV (7.65 ± 0.72, p = 0.02) or G0 (7.46 ± 0.31, p = 0.003). After 8 h Dox induction in pH 6.8 media, both G1- (6.21 ± 0.26) and G2-expressing cells had shorter mitochondria (6.46 ± 0.34) than cells expressing EV (7.13 ± 0.32, p = 0.002 and p = 0.008, respectively) or G0 (7.22 ± 0.45, p = 0.003 and p = 0.01, respectively). Mitochondrial length in cells incubated in pH 7.4 media were comparable after 8 h Dox induction regardless of genotype. APOL1 mRNA expression and cell viability were comparable regardless of pH or genotype after 8 h Dox induction. CONCLUSION: Acidic pH facilitates early mitochondrial dysfunction induced by APOL1 G1 and G2 KRVs in HEK293 cells. We propose that the acidic kidney interstitium may play a role in APOL1-mediated mitochondrial pathophysiology and nephropathy.

9.
Nat Genet ; 52(9): 969-983, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32839606

RESUMO

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Genoma/genética , LDL-Colesterol/genética , Simulação por Computador , Estudo de Associação Genômica Ampla/métodos , Humanos , Modelos Genéticos , Anotação de Sequência Molecular/métodos , Fenótipo , Sequenciamento Completo do Genoma/métodos
10.
Curr Diab Rep ; 20(10): 49, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32857243

RESUMO

PURPOSE OF REVIEW: This review focuses on the relationships between diabetes, cognitive impairment, and the contribution of kidney disease. RECENT FINDINGS: We review the independent contributions of parameters of kidney disease, including albuminuria, glomerular filtration, bone/mineral metabolism, and vitamin D synthesis, on cognitive performance in patients with diabetes. Potential pathophysiologic mechanisms underlying these associations are discussed highlighting gaps in existing knowledge. Finally, effects of the dialysis procedure on the brain and cognitive performance are considered. Emphasis is placed on novel non-invasive screening tools with the potential to preserve cerebral perfusion during hemodialysis and limit cognitive decline in patients with diabetic ESKD. Patients with type 2 diabetes and advanced chronic kidney disease suffer a higher prevalence of cognitive impairment. This is particularly true in patients with diabetes and end-stage kidney disease (ESKD).

11.
Clin J Am Soc Nephrol ; 15(8): 1121-1128, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32669306

RESUMO

BACKGROUND AND OBJECTIVES: It is unclear whether the presence of albuminuria modifies the effects of intensive systolic BP control on risk of eGFR decline, cardiovascular events, or mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Systolic Blood Pressure Intervention Trial randomized nondiabetic adults ≥50 years of age at high cardiovascular risk to a systolic BP target of <120 or <140 mm Hg, measured by automated office BP. We compared the absolute risk differences and hazard ratios of ≥40% eGFR decline, the Systolic Blood Pressure Intervention Trial primary cardiovascular composite outcome, and all-cause death in those with or without baseline albuminuria (urine albumin-creatinine ratio ≥30 mg/g). RESULTS: Over a median follow-up of 3.1 years, 69 of 1723 (4%) participants with baseline albuminuria developed ≥40% eGFR decline compared with 61 of 7162 (1%) participants without albuminuria. Incidence rates of ≥40% eGFR decline were higher in participants with albuminuria (intensive, 1.74 per 100 person-years; standard, 1.17 per 100 person-years) than in participants without albuminuria (intensive, 0.48 per 100 person-years; standard, 0.11 per 100 person-years). Although effects of intensive BP lowering on ≥40% eGFR decline varied by albuminuria on the relative scale (hazard ratio, 1.48; 95% confidence interval, 0.91 to 2.39 for albumin-creatinine ratio ≥30 mg/g; hazard ratio, 4.55; 95% confidence interval, 2.37 to 8.75 for albumin-creatinine ratio <30 mg/g; P value for interaction <0.001), the absolute increase in ≥40% eGFR decline did not differ by baseline albuminuria (incidence difference, 0.38 events per 100 person-years for albumin-creatinine ratio ≥30 mg/g; incidence difference, 0.58 events per 100 person-years for albumin-creatinine ratio <30 mg/g; P value for interaction =0.60). Albuminuria did not significantly modify the beneficial effects of intensive systolic BP lowering on cardiovascular events or mortality evaluated on relative or absolute scales. CONCLUSIONS: Albuminuria did not modify the absolute benefits and risks of intensive systolic BP lowering.

12.
J Am Soc Nephrol ; 31(9): 2122-2132, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32591439

RESUMO

BACKGROUND: Intensively treating hypertension may benefit cardiovascular disease and cognitive function, but at the short-term expense of reduced kidney function. METHODS: We investigated markers of kidney function and the effect of intensive hypertension treatment on incidence of dementia and mild cognitive impairment (MCI) in 9361 participants in the randomized Systolic Blood Pressure Intervention Trial, which compared intensive versus standard systolic BP lowering (targeting <120 mm Hg versus <140 mm Hg, respectively). We categorized participants according to baseline and longitudinal changes in eGFR and urinary albumin-to-creatinine ratio. Primary outcomes were occurrence of adjudicated probable dementia and MCI. RESULTS: Among 8563 participants who completed at least one cognitive assessment during follow-up (median 5.1 years), probable dementia occurred in 325 (3.8%) and MCI in 640 (7.6%) participants. In multivariable adjusted analyses, there was no significant association between baseline eGFR <60 ml/min per 1.73 m2 and risk for dementia or MCI. In time-varying analyses, eGFR decline ≥30% was associated with a higher risk for probable dementia. Incident eGFR <60 ml/min per 1.73 m2 was associated with a higher risk for MCI and a composite of dementia or MCI. Although these kidney events occurred more frequently in the intensive treatment group, there was no evidence that they modified or attenuated the effect of intensive treatment on dementia and MCI incidence. Baseline and incident urinary ACR ≥30 mg/g were not associated with probable dementia or MCI, nor did the urinary ACR modify the effect of intensive treatment on cognitive outcomes. CONCLUSIONS: Among hypertensive adults, declining kidney function measured by eGFR is associated with increased risk for probable dementia and MCI, independent of the intensity of hypertension treatment.

13.
Artigo em Inglês | MEDLINE | ID: mdl-32551134

RESUMO

Background: Although older adults encompass almost half of patients with advanced chronic kidney disease, it remains unclear which long-term hemodialysis vascular access type, arteriovenous fistula or arteriovenous graft, is optimal with respect to effectiveness and patient satisfaction. Clinical outcomes based on the initial AV access type have not been evaluated in randomized controlled trials. This pilot study tested the feasibility of randomizing older adults with advanced kidney disease to initial arteriovenous fistula versus graft vascular access surgery. Methods: Patients 65 years or older with pre-dialysis chronic kidney disease or incident end-stage kidney disease and no prior arteriovenous vascular access intervention were randomized in a 1:1 ratio to undergo surgical placement of a fistula or a graft after providing informed consent. Trial feasibility was evaluated as (i) recruitment of ≥ 70% of eligible participants, (ii) ≥ 50 to 70% of participants undergo placement of index arteriovenous access within 90 to 180 days of enrollment, respectively, (iii) ≥ 80% adherence to study-related assessments, and (iv) ≥ 70% of participants who underwent index arteriovenous access placement will have a follow-up duration of ≥ 12 months after index surgery date. Results: Between September 2018 and October 2019, 81% (44/54) of eligible participants consented and were enrolled in the study; 11 had pre-dialysis chronic kidney disease, and 33 had incident or prevalent end-stage kidney disease. After randomization, 100% (21/21) assigned to arteriovenous fistula surgery and 78% (18/23) assigned to arteriovenous graft surgery underwent index arteriovenous access placement within a median (1st, 3rd quartile) of 5.0 (1.0, 14.0) days and 13.0 (5.0, 44.3) days, respectively, after referral to vascular surgery. The completion rates for study-specific assessments ranged between 40.0 and 88.6%. At median follow-up of 215.0 days, 5 participants expired, 7 completed 12 months of follow-up, and 29 are actively being followed. Assessments of grip strength, functional independence, and vascular access satisfaction were completed by > 85% of patients who reached pre-specified post-operative assessment time point. Conclusions: Results from this study reveal it is feasible to enroll and randomize older adults with advanced kidney disease to one of two different arteriovenous vascular access placement surgeries. The study can progress with minor protocol adjustments to a multisite clinical trial. Trial registration: Clinical Trials ID, NCT03545113.

14.
Kidney Int Rep ; 5(6): 891-904, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32518871

RESUMO

Introduction: APOL1 G1 and G2 nephropathy-risk variants cause mitochondrial dysfunction and contribute to kidney disease. Analyses were performed to determine the genetic regulation of APOL1 and elucidate potential mechanisms in APOL1-nephropathy. Methods: A global gene expression analysis was performed in human primary renal tubule cell lines derived from 50 African American individuals. Follow-up gene knock out, cell-based rescue, and microscopy experiments were performed. Results: APOL1 genotypes did not alter APOL1 expression levels in the global gene expression analysis. Expression quantitative trait locus (eQTL) analysis in polyinosinic-polycytidylic acid (poly IC)-stimulated renal tubule cells revealed that single nucleotide polymorphism (SNP) rs513349 adjacent to BAK1 was a trans eQTL for APOL1 and a cis eQTL for BAK1; APOL1 and BAK1 were co-expressed in cells. BAK1 knockout in a human podocyte cell line resulted in diminished APOL1 protein, supporting a pivotal effect for BAK1 on APOL1 expression. Because BAK1 is involved in mitochondrial dynamics, mitochondrial morphology was examined in primary renal tubule cells and HEK293 Tet-on cells of various APOL1 genotypes. Mitochondria in APOL1 wild-type (G0G0) tubule cells maintained elongated morphology when stimulated by low-dose poly IC, whereas those with G1G1, G2G2, and G1G2 genotypes appeared to fragment. HEK293 Tet-on cells overexpressing APOL1 G0, G1, and G2 were created; G0 cells appeared to promote mitochondrial fusion, whereas G1 and G2 induced mitochondrial fission. The mitochondrial dynamic regulator Mdivi-1 significantly preserved cell viability and mitochondrial cristae structure and reversed mitochondrial fission induced by overexpression of G1 and G2. Conclusion: Results suggest the mitochondrial fusion/fission pathway may be a therapeutic target in APOL1-nephropathy.

16.
Clin J Am Soc Nephrol ; 15(3): 349-358, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32111704

RESUMO

BACKGROUND AND OBJECTIVES: eGFR and albuminuria primarily reflect glomerular function and injury, whereas tubule cell atrophy and interstitial fibrosis on kidney biopsy are important risk markers for CKD progression. Kidney tubule injury markers have primarily been studied in hospitalized AKI. Here, we examined the association between urinary kidney tubule injury markers at baseline with subsequent loss of kidney function in persons with nondiabetic CKD who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 2428 SPRINT participants with CKD (eGFR<60 ml/min per 1.73 m2) at baseline, we measured urine markers of tubule injury (IL-18, kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL]), inflammation (monocyte chemoattractant protein-1 [MCP-1]), and repair (human cartilage glycoprotein-40 [YKL-40]). Cox proportional hazards models evaluated associations of these markers with the kidney composite outcome of 50% eGFR decline or ESKD requiring dialysis or kidney transplantation, and linear mixed models evaluated annualized change in eGFR. RESULTS: Mean participant age was 73±9 (SD) years, 60% were men, 66% were white, and mean baseline eGFR was 46±11 ml/min per 1.73 m2. There were 87 kidney composite outcome events during a median follow-up of 3.8 years. Relative to the respective lowest quartiles, the highest quartiles of urinary KIM-1 (hazard ratio, 2.84; 95% confidence interval [95% CI], 1.31 to 6.17), MCP-1 (hazard ratio, 2.43; 95% CI, 1.13 to 5.23), and YKL-40 (hazard ratio, 1.95; 95% CI, 1.08 to 3.51) were associated with higher risk of the kidney composite outcome in fully adjusted models including baseline eGFR and urine albumin. In linear analysis, urinary IL-18 was the only marker associated with eGFR decline (-0.91 ml/min per 1.73 m2 per year for highest versus lowest quartile; 95% CI, -1.44 to -0.38), a finding that was stronger in the standard arm of SPRINT. CONCLUSIONS: Urine markers of tubule cell injury provide information about risk of subsequent loss of kidney function, beyond the eGFR and urine albumin.

17.
Kidney Int Rep ; 5(3): 278-288, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32154449

RESUMO

Introduction: Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)-sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes. Methods: APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. Results: The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. Conclusion: This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation.

18.
Clin Transplant ; 34(6): e13827, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32080893

RESUMO

Two renal-risk variants in the apolipoprotein L1 gene (APOL1) in African American (AA) deceased donors (DD) are associated with shorter renal allograft survival after transplantation. To identify additional genes contributing to allograft survival, a genome-wide association study was performed in 532 AA DDs. Phenotypic data were obtained from the Scientific Registry of Transplant Recipients. Association and single-nucleotide polymorphism (SNP)-by-APOL1 interaction tests were conducted using death-censored renal allograft survival accounting for relevant covariates. Replication and inverse-variance-weighted meta-analysis were performed using data from 250 AA DD in the Genomics of Transplantation study. Accounting for APOL1, multiple SNPs near the Nudix Hydrolase 7 gene (NUDT7) showed strong independent effects (P = 1.6 × 10-8 -2.2 × 10-8 ). Several SNPs in the Translocation protein SEC63 homolog (SEC63; P = 2 × 10-9 -3.7 × 10-8 ) and plasmacytoma variant translocation 1 (PVT1) genes (P = 4.0 × 10-8 -7 × 10-8 ) modified the effect of APOL1 on allograft survival. SEC63 is expressed in human renal tubule cells and glomeruli, and PVT1 is associated with diabetic kidney disease. Overall, associations were detected for 41 SNPs (P = 2 × 10-9 -5 × 10-8 ) contributing independently or interacting with APOL1 to impact renal allograft survival after transplantation from AA DD. Given the small sample size of the discovery and replication sets, independent validations and functional genomic efforts are needed to validate these results.

19.
J Electrocardiol ; 58: 150-154, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31895990

RESUMO

BACKGROUND: QRS-duration predicts mortality in patients with heart failure and, to a lesser extent, the general population. However, in patients with diabetes, its prognostic significance is unknown. To better understand how QRS-duration relates to mortality among those with diabetes, we explored survival as a function of QRS-duration in the Diabetes Heart Study. METHODS: The study population included 1335 participants. Cox proportional hazards modeling was used to evaluate the relationship between QRS-duration and all-cause mortality, comparing those with QRS-duration ≤120 vs. >120 (ms). Multivariable models adjusted for age, sex, race, hypertension, smoking, years with diabetes, BMI, systolic blood pressure, cholesterol, triglycerides, glomerular filtration rate, and hemoglobin A1c. RESULTS AND CONCLUSIONS: Participants were: mean age 61 ± 9, 55% women, 83% white; 99 participants (7.5%) had a QRS-duration >120. After 11,000 person-years of follow-up (median 8.5 years; maximum 13.9 years), 266 participants had died (20%). Participants with baseline QRS-duration >120 had an adjusted hazard ratio for all-cause mortality of 1.56 (95% CI 1.05-2.24; p = 0.027). Modeling QRS-duration as a continuous variable, we found an 11% increase in all-cause mortality for each 10 ms increase in QRS-duration. In conclusion, QRS-duration is associated with subsequent all-cause mortality among those with type 2 diabetes-participants with QRS-duration >120 ms had a 56% increase in all-cause mortality, even after adjustment for conventional risk factors. Given the ubiquitous presence of ECG data in the medical record, QRS-duration may prove to be a useful prognostic measure, especially among those with diabetes.

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