Long-term outcomes of metallic endobronchial stents in lung transplant recipients are not affected by bacterial colonization.

OBJECTIVES: We evaluated associations of endobronchial stenting with airway bacterial colonization, the antimicrobial resistance profile, hospitalizations for pneumonia and survival in lung transplant recipients. METHODS: This is a retrospective single-centre study of 582 recipients of lung transplant during 2002-2018. We compared outcomes of 57 patients (9.7%) who received endobronchial stents (intervention group) to a control group of 57 patients without stents who were matched one to one for age, sex, year of transplantation, unilateral/bilateral transplantation and underlying disease. RESULTS: For the intervention compared to the control group, airway colonization was more common for Pseudomonas (86% vs 35%, P < 0.001), Acinetobacter (21% vs 7%, P = 0.05), Klebsiella (21% vs 5%, P = 0.02) and Staphylococcus species (11% vs 0%, P = 0.02). The respective proportions of patients with positive bronchoalveolar lavage cultures on the third post-transplantation day, the day of stent insertion and 6-month post-stent insertion were 47.4%, 50.9% and 65.4% for Pseudomonas sp.; 15.8%, 12.3% and 3.8% for Klebsiella sp.; and 8.8%, 5.3% and 5.8% for Acinetobacter sp. The mean number of hospitalizations for pneumonia per patient was higher, without statistical significance, in the intervention than the control group (1.5 ± 1.7 vs 0.9 ± 1.5, P = 0.1). Kaplan-Meier survival curves did not show a statistically significant difference between the intervention group and the entire group without endobronchial stents (n = 525) (P = 0.4). CONCLUSIONS: Lung transplant recipients with endobronchial stents were more likely to be colonized with pathologic bacteria and having pneumonia; however, stent placement was not associated with increased long-term mortality with appropriate stent maintenance.

The Etiology and Prognosis of Delayed Postoperative Leukocytosis in Lung Transplant Recipients.

BACKGROUND: Leukocytosis (white blood cell count >12 000/µL) in the delayed postoperative period (4-7 days) after lung transplantation is due to diverse etiologies. We aimed to describe the etiologies of delayed postoperative leukocytosis in lung transplant recipients and to evaluate the association of leukocytosis causes with short-term survival. METHODS: A retrospective chart review of 274 lung transplantations performed in our institution during 2006 to 2013. RESULTS: Delayed postoperative leukocytosis was seen in 159 (58.0%) of lung transplant recipients. In 57 (35.8%) of them, the etiology of the leukocytosis was not identified. The etiologies of leukocytosis that were identified were infection (n = 39), second surgery, acute rejection (n = 12), primary graft dysfunction (n = 3), multiple etiologies (n = 17), and other causes (n = 10). On multivariate analysis, delayed postoperative leukocytosis was one of the variables that most significantly associated with decreased survival in the entire sample (hazard ratio [HR] = 1.52, 95% confidence interval [CI]: 1.01-2.29, P = .040). On additional analysis for mortality assessing each leukocytosis subgroup, the data were acute graft rejection (HR = 8.21, 95% CI: 4.09-16.49, P < .001), second surgery (HR = 2.05, 95% CI: 1.08-3.90, P = .020), primary graft dysfunction (HR = 2.72, 95% CI: 0.65-11.33, P = .169), other causes (HR = 1.30, 95% CI: 0.47-3.62, P = .620), and unknown etiology (HR = 0.94, 95% CI: 0.54-1.62, P = .800). CONCLUSIONS: Delayed post-lung transplant leukocytosis is a poor prognostic sign, especially when attributed to acute graft rejection, infection, and multiple etiologies. In the absence of an identifiable etiology, it can be attributed to postoperative reactive stress, is not associated with increased mortality, and likely does not warrant further diagnostic investigation.

G1 is the major APOL1 risk allele for hypertension-attributed nephropathy in Central Africa.

BACKGROUND: Sub-Saharan Africans exhibit a higher frequency of chronic kidney disease (CKD) than other populations. In this study, we sought to determine the frequency of apolipoprotein L1 (APOL1) genotypes in hypertension-attributed CKD in Kinshasa, Democratic Republic of the Congo. METHODS: We performed a case-control study identifying 162 subjects: 79 with hypertension-attributed CKD and 83 controls living in Kinshasa who were genotyped for APOL1 risk variants between July 2013 and November 2016. We selected control subjects from the general population and matched them with the cases according to age. Logistic regression analysis was used to examine the relationship between APOL1 high-risk genotypes and CKD. RESULTS: The frequencies of the APOL1 G1 and G2 alleles were 19.1 and 7.1%, respectively. The number of individuals with the G1 and G2 risk alleles was significantly higher in the CKD group (12.7%) than in the control group (2.4%), particularly in individuals with end-stage kidney disease (14.3%). Subjects carrying two risk alleles was strongly and independently associated with hypertension-attributed nephropathy, with an adjusted odds ratio of 7.7 (95% confidence interval 1.5-39.7; P = 0.014). The high-risk APOL1 genotypes were G1/G1 and G1/G2, whereas G2/G2 was not found in the study population. CONCLUSIONS: The results of this study demonstrate the association of high-risk APOL1 genotypes with kidney disease in Kinshasa. The absence of G2/G2 may be consistent with powerful selective sweeps induced by Trypanosoma brucei gambiense infection. In contrast, the presence of APOL1 G2/G2 among individuals of African ancestry in the USA may indicate relaxation of natural selection in a trypanosome-free environment.

Emergence of an Israel faith-based community organization facilitating live donor kidney transplantation.

BACKGROUND: The 2014 Consensus Conference on Best Practices in Living Kidney Donations recognized live donor kidney transplantation as the best treatment for late-stage kidney disease, yielding superior graft and patient survival, improved quality of life, fewer requirements for dialysis and increased cost-effectiveness compared to deceased donor kidney transplantation. Yet in spite of the excellent results of living kidney donation, the annual number of living kidney donors is declining in many countries, including the United States. In Israel, a non-profit organization, Matnat Chaim ("Gift of Life" in Hebrew), a faith-based initiative, has emerged as a major force for arranging living donor kidney transplantation mainly by facilitating altruistic living unrelated donor transplantation. METHODS: A retrospective review of the records of live kidney donations facilitated by the Matnat Chaim organization and referred to Israel transplant centers, since the organization's inception in 2009, was performed and compared to published data from the Israel Ministry of Health. RESULTS: Matnat Chaim has facilitated 494 live kidney donations since its founding in February 2009 until the end of 2017. Of the 124 live kidney transplants performed in 2016, 111 (90%) were shown to be altruistic and unrelated. This large number of donations was associated with a doubling of the total number of kidney transplantations, performed in Israel (data published by the Israel Ministry of Health). CONCLUSIONS: The success of an Israel community organization in the promotion of kidney transplantation may serve as a model for other religious and non-religious communities worldwide.

A null variant in the apolipoprotein L3 gene is associated with non-diabetic nephropathy.

Background: Inheritance of apolipoprotein L1 gene (APOL1) renal-risk variants in a recessive pattern strongly associates with non-diabetic end-stage kidney disease (ESKD). Further evidence supports risk modifiers in APOL1-associated nephropathy; some studies demonstrate that heterozygotes possess excess risk for ESKD or show earlier age at ESKD, relative to those with zero risk alleles. Nearby loci are also associated with ESKD in non-African Americans. Methods: We assessed the role of the APOL3 null allele rs11089781 on risk of non-diabetic ESKD. Four cohorts containing 2781 ESKD cases and 2474 controls were analyzed. Results: Stratifying by APOL1 risk genotype (recessive) and adjusting for African ancestry identified a significant additive association between rs11089781 and ESKD in each stratum and in a meta-analysis [meta-analysis P = 0.0070; odds ratio (OR) = 1.29]; ORs were consistent across APOL1 risk strata. The biological significance of this association is supported by the finding that the APOL3 gene is co-regulated with APOL1, and that APOL3 protein was able to bind to APOL1 protein. Conclusions: Taken together, the genetic and biological data support the concept that other APOL proteins besides APOL1 may also influence the risk of non-diabetic ESKD.

APOL1 Nephropathy: A Population Genetics and Evolutionary Medicine Detective Story.

Common DNA sequence variants rarely have a high-risk association with a common disease. When such associations do occur, evolutionary forces must be sought, such as in the association of apolipoprotein L1 (APOL1) gene risk variants with nondiabetic kidney diseases in populations of African ancestry. The variants originated in West Africa and provided pathogenic resistance in the heterozygous state that led to high allele frequencies owing to an adaptive evolutionary selective sweep. However, the homozygous state is disadvantageous and is associated with a markedly increased risk of a spectrum of kidney diseases encompassing hypertension-attributed kidney disease, focal segmental glomerulosclerosis, human immunodeficiency virus nephropathy, sickle cell nephropathy, and progressive lupus nephritis. This scientific success story emerged with the help of the tools developed over the past 2 decades in human genome sequencing and population genomic databases. In this introductory article to a timely issue dedicated to illuminating progress in this area, we describe this unique population genetics and evolutionary medicine detective story. We emphasize the paradox of the inheritance mode, the missing heritability, and unresolved associations, including cardiovascular risk and diabetic nephropathy. We also highlight how genetic epidemiology elucidates mechanisms and how the principles of evolution can be used to unravel conserved pathways affected by APOL1 that may lead to novel therapies. The APOL1 gene provides a compelling example of a common variant association with common forms of nondiabetic kidney disease occurring in a continental population isolate with subsequent global admixture. Scientific collaboration using multiple experimental model systems and approaches should further clarify pathomechanisms further, leading to novel therapies.

Effect of hemodialysis access blood flow on cardiac events after coronary artery bypass grafting using an internal thoracic artery.

BACKGROUND: The possibility of coronary steal through an arteriovenous fistula (AVF) in hemodialysis (HD) patients with coronary artery bypass grafts (CABGs) using an ipsilateral internal thoracic artery (ITA) has been suggested. In order to define the significance of such a possibility, we analyzed cardiac events and mortality risk in patients in relation to AVF flow. METHODS: A retrospective cohort study was performed on prevalent HD patients from a single center. The outcomes included a first cardiac event, cardiac death and death from any cause. RESULTS: The group consisted of 23 chronic HD patients having ITA CABG and upper extremity AV access, 12 patients had an ipsilateral and 11 patients had a contralateral location of ITA CABG and an upper extremity AV access. The mean follow-up period was for 37.0 months.Multivariable Cox proportional-hazards regression analysis of risk of death from any cause in relation to AV access flow showed no increased risk, neither in the group with ipsilateral location of ITA grafts and dialysis accesses (adjusted HR, 3.047 [95% CI, 0.996 to 1.000], p = 0.081), nor in the group with contralateral location of both shunts (adjusted HR, 0.173 [95% CI, 0.997 to 1.002], p = 0.678). There was no significant correlation between AV access blood flow and the risk of first cardiac event as well as cardiac death in either study group. CONCLUSIONS: In this study on HD patients having ipsilateral ITA CABG and AVF, fistula flow rate was not found to be associated with mortality or cardiac risk.

APOL1-Mediated Cell Injury Involves Disruption of Conserved Trafficking Processes.

APOL1 harbors C-terminal sequence variants (G1 and G2), which account for much of the increased risk for kidney disease in sub-Saharan African ancestry populations. Expression of the risk variants has also been shown to cause injury to podocytes and other cell types, but the underlying mechanisms are not understood. We used Drosophila melanogaster and Saccharomyces cerevisiae to help clarify these mechanisms. Ubiquitous expression of the human APOL1 G1 and G2 disease risk alleles caused near-complete lethality in D. melanogaster, with no effect of the G0 nonrisk APOL1 allele, corresponding to the pattern of human disease risk. We also observed a congruent pattern of cellular damage with tissue-specific expression of APOL1. In particular, expression of APOL1 risk variants in D. melanogaster nephrocytes caused cell-autonomous accumulation of the endocytic tracer atrial natriuretic factor-red fluorescent protein at early stages and nephrocyte loss at later stages. We also observed differential toxicity of the APOL1 risk variants compared with the APOL1 nonrisk variants in S. cerevisiae, including impairment of vacuole acidification. Yeast strains defective in endosomal trafficking or organelle acidification but not those defective in autophagy displayed augmented APOL1 toxicity with all isoforms. This pattern of differential injury by the APOL1 risk alleles compared with the nonrisk alleles across evolutionarily divergent species is consistent with an impairment of conserved core intracellular endosomal trafficking processes. This finding should facilitate the identification of cell injury pathways and corresponding therapeutic targets of interest in these amenable experimental platforms.

Erratum to "Endobronchial Enigma: A Clinically Rare Presentation of Nocardia beijingensis in an Immunocompetent Patient".

[This corrects the article DOI: 10.1155/2015/970548.].

The Diagnostic Value of the Pleural Fluid C-Reactive Protein in Parapneumonic Effusions.

Purpose. The aim of this study was to evaluate the sensitivity of pleural C-reactive protein (CRP) biomarker levels in identifying parapneumonic effusions. Methods. A single-center, retrospective review of 244 patients diagnosed with pleural effusions was initiated among patients at the Rabin Medical Center, Petah Tikva, Israel, between January 2011 and December 2013. The patients were categorized into 4 groups according to their type of pleural effusion as follows: heart failure, malignant, post-lung transplantation, and parapneumonic effusion. Results. The pleural CRP levels significantly differentiated the four groups (p < 0.001) with the following means: parapneumonic effusion, 5.38 ± 4.85 mg/dL; lung transplant, 2.77 ± 2.66 mg/dL; malignancy, 1.19 ± 1.51 mg/dL; and heart failure, 0.57 ± 0.81 mg/dL. The pleural fluid CRP cut-off value for differentiating among parapneumonic effusions and the other 3 groups was 1.38 mg/dL. The sensitivity, specificity, positive predictive value, and negative predictive value were 84.2%, 71.5%, 37%, and 95%, respectively. A backward logistic regression model selected CRP as the single predictor of parapneumonic effusion (OR = 1.59, 95% CI = 1.37-1.89). Conclusions. Pleural fluid CRP levels can be used to distinguish between parapneumonic effusions and other types of exudative effusions. CRP levels < 0.64 mg/dL are likely to indicate a pleural effusion from congestive heart failure, whereas levels ≥ 1.38 mg/dL are suggestive of an infectious etiology.

Effect of Jewish-Arab Ancestry and Gender Matching on Clinical Outcome of Lung Transplantation in Israel.

BACKGROUND: Studies in lung transplantation demonstrate that the ancestry and gender dissimilarities of donor-recipients lead to a decrease in survival of the recipient. OBJECTIVES: To evaluate the survival of lung transplant recipients in Israel based on whether the donors and recipients are of Jewish or Arab ancestry as well as survival based on gender match or mismatch. METHODS: We performed a retrospective observational cohort study of 345 lung transplant recipients at the Rabin Medical Center, Petah Tikva, Israel between January 1997 and January 2013. We compared the survival of lung transplant recipients in two ancestry categories: ancestry matched (Jewish donors to Jewish recipients or Arab donors to Arab recipients) and ancestry mismatched (Jewish donors to Arab recipients and vice versa). We also compared the survival among the four gender donor and recipient combinations (male to male, female to female, male to female, and female to male). RESULTS: Survival analysis revealed no significant differences between the two ancestry groups (P = 0.51) and among the four gender combinations (P = 0.58). On Cox multivariate analysis, younger donor age was the only significant parameter for longer survival (hazards ratio 1.025, 95% confidence interval 1.012-1.037). CONCLUSIONS: Gender and ancestry mismatches in these two Israeli populations do not appear to alter the clinical outcomes following lung transplantation.

APOL1 nephropathy: from gene to mechanisms of kidney injury.

The contribution of African ancestry to the risk of focal segmental glomerulosclerosis and chronic kidney disease has been partially explained by the recently described chromosome 22q variants in the gene apolipoprotein L1 (APOL1). The APOL1 variants appear at a high allele frequency in populations of West African ancestry as a result of apparent adaptive selection of the heterozygous state. Heterozygosity protects from infection with Trypanosoma brucei rhodesiense. This review will describe the role of the approaches in population genetics for the description of APOL1-associated nephropathies and draw inferences as to the biologic mechanisms from genetic epidemiology findings to date. Modifier loci can influence APOL1 risk for the development of kidney disease. 'Second hits', both viral and non-viral, may explain the discrepancy between the remarkably high odds ratios and the low lifetime risks of kidney disease in two allele carriers of APOL1 risk variants. Therapeutic strategies for APOL1-associated nephropathies will require the prevention and treatment of these 'second hits' and the development of drugs to protect the APOL1 downstream renal injury pathways.

Association of APOL1 Genotype with Renal Histology among Black HIV-Positive Patients Undergoing Kidney Biopsy.

BACKGROUND AND OBJECTIVES: Prior studies have shown that the APOL1 risk alleles are associated with a greater risk of HIV-associated nephropathy and FSGS among blacks who are HIV positive. We sought to determine whether the APOL1 high-risk genotype incrementally improved the prediction of these underlying lesions beyond conventional clinical factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cross-sectional study, we analyzed data from 203 blacks who are HIV positive, underwent kidney biopsies between 1996 and 2011, and were genotyped for the APOL1 G1 and G2 alleles. Predictive logistic regression models with conventional clinical factors were compared with those that also included APOL1 genotype using receiver-operating curves and bootstrapping analyses with crossvalidation. RESULTS: The addition of APOL1 genotype to HIV-related risk factors for kidney disease in a predictive model improved the prediction of non-HIV-associated nephropathy FSGS, specifically, increasing the c statistic from 0.65 to 0.74 (P=0.04). Although two risk alleles were significantly associated with higher odds of HIV-associated nephropathy, APOL1 genotype did not add incrementally to the prediction of this specific histopathology. CONCLUSIONS: APOL1 genotype may provide additional diagnostic information to traditional clinical variables in predicting underlying FSGS spectrum lesions in blacks who are HIV positive. In contrast, although APOL1 risk genotype predicts HIV-associated nephropathy, it lacked a high c statistic sufficient for discrimination to eliminate the role of kidney biopsy in the clinical care of blacks who are HIV positive with nephrotic proteinuria or unexplained kidney disease.

The Envy of Scholars: Applying the Lessons of the Framingham Heart Study to the Prevention of Chronic Kidney Disease.

During the past 50 years, a dramatic reduction in the mortality rate associated with cardiovascular disease has occurred in the US and other countries. Statistical modeling has revealed that approximately half of this reduction is the result of risk factor mitigation. The successful identification of such risk factors was pioneered and has continued with the Framingham Heart Study, which began in 1949 as a project of the US National Heart Institute (now part of the National Heart, Lung, and Blood Institute). Decreases in total cholesterol, blood pressure, smoking, and physical inactivity account for 24%, 20%, 12%, and 5% reductions in the mortality rate, respectively. Nephrology was designated as a recognized medical professional specialty a few years later. Hemodialysis was first performed in 1943. The US Medicare End-Stage Renal Disease (ESRD) Program was established in 1972. The number of patients in the program increased from 5,000 in the first year to more than 500,000 in recent years. Only recently have efforts for risk factor identification, early diagnosis, and prevention of chronic kidney disease (CKD) been undertaken. By applying the approach of the Framingham Heart Study to address CKD risk factors, we hope to mirror the success of cardiology; we aim to prevent progression to ESRD and to avoid the cardiovascular complications associated with CKD. In this paper, we present conceptual examples of risk factor modification for CKD, in the setting of this historical framework.

Endobronchial Enigma: A Clinically Rare Presentation of Nocardia beijingensis in an Immunocompetent Patient.

Nocardiosis is an opportunistic infection caused by the Gram-positive weakly acid-fast, filamentous aerobic Actinomycetes. The lungs are the primary site of infection mainly affecting immunocompromised patients. In rare circumstances even immunocompetent hosts may also develop infection. Diagnosis of pulmonary nocardiosis is usually delayed due to nonspecific clinical and radiological presentations which mimic fungal, tuberculous, or neoplastic processes. The present report describes a rare bronchoscopic presentation of an endobronchial nocardial mass in a 55-year-old immunocompetent woman without underlying lung disease. The patient exhibited signs and symptoms of unresolving community-acquired pneumonia with a computed tomography (CT) scan that showed a space-occupying lesion and enlarged paratracheal lymph node. This patient represents the unusual presentation of pulmonary Nocardia beijingensis as an endobronchial mass. Pathology obtained during bronchoscopy demonstrated polymerase chain reaction (PCR) confirmation of nocardiosis. Symptoms and clinical findings improved with antibiotic treatment. This patient emphasizes the challenge in making the diagnosis of pulmonary nocardiosis, especially in a low risk host. A literature review presents the difficulties and pitfalls in the clinical assessment of such an individual.

High population frequencies of APOL1 risk variants are associated with increased prevalence of non-diabetic chronic kidney disease in the Igbo people from south-eastern Nigeria.

BACKGROUND: Continental Africa is facing an epidemic of chronic kidney disease (CKD). APOL1 risk variants have been shown to be strongly associated with an increased risk for non-diabetic kidney disease including HIV nephropathy, primary non-monogenic focal and segmental glomerulosclerosis, and hypertension-attributed nephropathy among African ancestry populations in the USA. The world's highest frequencies of APOL1 risk alleles have been reported in West African nations, overlapping regions with a high incidence of CKD and hypertension. One such region is south-eastern Nigeria, and therefore we sought to quantify the association of APOL1 risk alleles with CKD in this region. METHODS: APOL1 risk variants were genotyped in a case-control sample set consisting of non-diabetic, CKD patients (n = 44) and control individuals (n = 43) from Enugu and Abakaliki, Nigeria. RESULTS: We found a high frequency of two APOL1 risk alleles in the general population of Igbo people of south-eastern Nigeria (23.3%). The two APOL1 risk allele frequency in the CKD patient group was 66%. Logistic regression analysis under a recessive inheritance model showed a strong and significant association of APOL1 two-risk alleles with CKD, yielding an odds ratio of 6.4 (unadjusted p = 1.2E-4); following correction for age, gender, HIV and BMI, the odds ratio was 4.8 (adjusted p = 5.1E-03). CONCLUSION: APOL1 risk variants are common in the Igbo population of south-eastern Nigeria, and are also highly associated with non-diabetic CKD in this area. APOL1 may explain the increased prevalence of CKD in this region.

Hypertension-misattributed kidney disease in African Americans.

Lipkowitz et al. extend the African American Study of Kidney Disease and Hypertension to the level of genetic epidemiology, in a case-control study design. Analysis of genotypes at the APOL1 kidney disease risk region supports a paradigm shift in which genetic risk is proximate to both kidney disease and hypertension. The findings mandate urgency in clarifying mechanisms whereby APOL1 region risk variants interact with environmental triggers to cause progressive kidney disease accompanied by dangerous hypertension.

Linkage disequilibrium analysis reveals an albuminuria risk haplotype containing three missense mutations in the cubilin gene with striking differences among European and African ancestry populations.

BACKGROUND: A recent meta-analysis described a variant (p.Ile2984Val) in the cubilin gene (CUBN) that is associated with levels of albuminuria in the general population and in diabetics. METHODS: We implemented a Linkage Disequilibrium (LD) search with data from the 1000 Genomes Project, on African and European population genomic sequences. RESULTS: We found that the p.Ile2984Val variation is part of a larger haplotype in European populations and it is almost absent in west Africans. This haplotype contains 19 single nucleotide polymorphisms (SNPs) in very high LD, three of which are missense mutations (p.Leu2153Phe, p.Ile2984Val, p.Glu3002Gly), and two have not been previously reported. Notably, this European haplotype is absent in west African populations, and the frequency of each individual polymorphism differs significantly in Africans. CONCLUSIONS: Genotyping of these variants in existing African origin sample sets coupled to measurements of urine albumin excretion levels should reveal which is the most likely functional candidate for albuminuria risk. The unique haplotypic structure of CUBN in different populations may leverage the effort to identify the functional variant and to shed light on evolution of the CUBN gene locus.