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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.

MYH9 has been proposed as a major genetic risk locus for a spectrum of nondiabetic end stage kidney disease (ESKD). We use recently released sequences from the 1000 Genomes Project to identify two western African-specific missense mutations (S342G and I384M) in the neighboring APOL1 gene, and demonstrate that these are more strongly associated with ESKD than previously reported MYH9 variants. The APOL1 gene product, apolipoprotein L-1, has been studied for its roles in trypanosomal lysis, autophagic cell death, lipid metabolism, as well as vascular and other biological activities. We also show that the distribution of these newly identified APOL1 risk variants in African populations is consistent with the pattern of African ancestry ESKD risk previously attributed to MYH9. Mapping by admixture linkage disequilibrium (MALD) localized an interval on chromosome 22, in a region that includes the MYH9 gene, which was shown to contain African ancestry risk variants associated with certain forms of ESKD (Kao et al. 2008; Kopp et al. 2008). MYH9 encodes nonmuscle myosin heavy chain IIa, a major cytoskeletal nanomotor protein expressed in many cell types, including podocyte cells of the renal glomerulus. Moreover, 39 different coding region mutations in MYH9 have been identified in patients with a group of rare syndromes, collectively termed the Giant Platelet Syndromes, with clear autosomal dominant inheritance, and various clinical manifestations, sometimes also including glomerular pathology and chronic kidney disease (Kopp 2010; Sekine et al. 2010). Accordingly, MYH9 was further explored in these studies as the leading candidate gene responsible for the MALD signal. Dense mapping of MYH9 identified individual single nucleotide polymorphisms (SNPs) and sets of such SNPs grouped as haplotypes that were found to be highly associated with a large and important group of ESKD risk phenotypes, which as a consequence were designated as MYH9-associated nephropathies (Bostrom and Freedman 2010). These included HIV-associated nephropathy (HIVAN), primary nonmonogenic forms of focal segmental glomerulosclerosis, and hypertension affiliated chronic kidney disease not attributed to other etiologies (Bostrom and Freedman 2010). The MYH9 SNP and haplotype associations observed with these forms of ESKD yielded the largest odds ratios (OR) reported to date for the association of common variants with common disease risk (Winkler et al. 2010). Two specific MYH9 variants (rs5750250 of S-haplotype and rs11912763 of F-haplotype) were designated as most strongly predictive on the basis of Receiver Operating Characteristic analysis (Nelson et al. 2010). These MYH9 association studies were then also extended to earlier stage and related kidney disease phenotypes and to population groups with varying degrees of recent African ancestry admixture (Behar et al. 2010; Freedman et al. 2009a, b; Nelson et al. 2010), and led to the expectation of finding a functional African ancestry causative variant within MYH9. However, despite intensive efforts including re-sequencing of the MYH9 gene no suggested functional mutation has been identified (Nelson et al. 2010; Winkler et al. 2010). This led us to re-examine the interval surrounding MYH9 and to the detection of novel missense mutations with predicted functional effects in the neighboring APOL1 gene, which are significantly more associated with ESKD than all previously reported SNPs in MYH9.

Background The question of a genetic contribution to the higher prevalence and incidence of end stage kidney disease (ESKD) among African Americans (AA) remained unresolved, until recent findings using admixture mapping pointed to the association of a genomic locus on chromosome 22 with this disease phenotype. In the current study we utilize this example to demonstrate the utility of applying a multi-step admixture mapping approach. Methods A multi-step case only admixture mapping study, consisted of the following steps was designed: 1) Assembly of the sample dataset (ESKD AA); 2) Design of the estimated mutual information ancestry informative markers (n = 2016) screening panel 3); Genotyping the sample set whose size was determined by a power analysis (n = 576) appropriate for the initial screening panel; 4) Inference of local ancestry for each individual and identification of regions with increased AA ancestry using two different ancestry inference statistical approaches; 5) Enrichment of the initial screening panel; 6) Power analysis of the enriched panel 7) Genotyping of additional samples. 8) Re-analysis of the genotyping results to identify a genetic risk locus. Results The initial screening phase yielded a significant peak using the ADMIXMAP ancestry inference program applying case only statistics. Subgroup analysis of 299 ESKD patients with no history of diabetes yielded peaks using both the ANCESTRYMAP and ADMIXMAP ancestry inference programs. The significant peak was found on chromosome 22. Genotyping of additional ancestry informative markers on chromosome 22 that took into account linkage disequilibrium in the ancestral populations, and the addition of samples increased the statistical significance of the finding. Conclusions A multi-step admixture mapping analysis of AA ESKD patients replicated the finding of a candidate risk locus on chromosome 22, contributing to the heightened susceptibility of African Americans to develop non-diabetic ESKD, and underscores the importance of using mutual information and multiple ancestry inference approaches to achieve a robust analysis, using relatively small datasets of \"affected\" only individuals. The current study suggests solutions to some limitations of existing admixture mapping methodologies, such as considerations regarding the distribution of ancestry information along the genome and its effects on power calculations and sample size.

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.

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.

Population-based genetic studies initially identified MYH9 as a major susceptibility locus for diabetes-unrelated kidney diseases in persons of West African ancestry, but further research found more strongly associated mutations in the neighboring APOL1 gene. This Review describes how evolutionary selection pressure of an infectious pathogen in West Africa favored the spread of APOL1 variants that protect against a lethal form of African sleeping sickness but are associated with an increased risk of kidney disease. The authors discuss lessons that can be learned for future population genetics research. Many rare kidney disorders exhibit a monogenic, Mendelian pattern of inheritance. Population-based genetic studies have identified many genetic variants associated with an increased risk of developing common kidney diseases. Strongly associated variants have potential clinical uses as predictive markers and may advance our understanding of disease pathogenesis. These principles are elegantly illustrated by a region within chromosome 22q12 that has a strong association with common forms of kidney disease. Researchers had identified DNA sequence variants in this locus that were highly associated with an increased prevalence of common chronic kidney diseases in people of African ancestry. Initial research concentrated on MYH9 as the most likely candidate gene; however, population-based whole-genome analysis enabled two independent research teams to discover more strongly associated mutations in the neighboring APOL1 gene. The powerful evolutionary selection pressure of an infectious pathogen in West Africa favored the spread of APOL1 variants that protect against a lethal form of African sleeping sickness but are highly associated with an increased risk of kidney disease. We describe the data sources, process of discovery, and reasons for initial misidentification of the candidate gene, as well as the lessons that can be learned for future population genetics research. Key Points Population genetic studies have identified loci that confer susceptibility to many common forms of kidney disease; however, ascertaining the underlying biologic mechanisms is often a challenge Linkage disequilibrium, admixture and genetic variation are some of the key factors underlying the success of population-based approaches to the discovery of genes that are associated with disease Population genetics research identified a region on chromosome 22q12 containing DNA sequence variants associated with a predisposition to many diabetes-unrelated forms of kidney disease in African and Hispanic Americans The MYH9 gene was initially thought to harbor these mutations, but the neighboring gene APOL1 was subsequently identified as being more strongly associated with kidney disease APOL1 mutations confer protection against sleeping sickness, which might explain the high prevalence of kidney disease in persons whose ancestry links them to geographic regions with past trypanosomal exposure APOL1 genotyping has potential clinical applications for management of hypertension in individuals with kidney disease, management of patients with HIV-associated nephropathy, and for donors and recipients in kidney transplantation

In the article titled “Endobronchial Enigma: A Clinically Rare Presentation of Nocardia beijingensis in an Immunocompetent Patient,” [1] the name of the second author was given incorrectly as Shimon Izhakain. The author’s name should have been written Shimon Izhakian. The revised author list is shown above.

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. Copyright © 2013 S. Karger AG, Basel [PUBLICATION ABSTRACT]

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.

Background: Susceptibility to end-stage kidney disease (ESKD) among HIV-infected Americans of African ancestral heritage has been attributed to APOL1 genetic variation. We determined the frequency of the APOL1 G1 and G2 risk variants together with the prevalence of HIV-associated nephropathy (HIVAN) among individuals of Ethiopian ancestry to determine whether the kidney disease genetic risk is PanAfrican or restricted to West Africa, and can explain the previously reported low risk of HIVAN among Ethiopians. Methods: We studied a cohort of 338 HIV-infected individuals of Ethiopian ancestry treated in one Israeli and one Ethiopian center. We sought clinical evidence for HIVAN (serum creatinine >1.4 mg/dl or proteinuria >30 mg/dl in a spot urine sample). Genetic analyses included the genotyping of the APOL1 G1 and G2 variants, and a panel of 33 genomic ancestry-informative markers. Statistical analysis compared clinical and genetic indices for HIV-infected individuals of Ethiopian ancestry and overall Ethiopians to those reported for HIV-infected African-Americans, overall African-Americans, West Africans and non-Africans. Findings: Three (0.8%) of 338 HIV-infected patients of Ethiopian ancestry showed clinical criteria compatible with renal impairment. Two of these 3 patients also have severe poorly controlled diabetes mellitus. The third nondiabetic patient underwent renal biopsy which ruled out HIVAN. This absence of clinically apparent HIVAN was significantly different from that reported for African-Americans. The APOL1 G1 and G2 risk variants were found, respectively, in 0 and 2 (heterozygote state) of the 338 HIV-infected individuals. Global ancestry and the frequencies of the APOL1 G1 and G2 variants are not statistically different from their frequencies in the general Ethiopian population, but are significantly and dramatically lower than those observed among HIV-infected African-Americans, African-Americans and West Africans. Interpretation: The coinciding absence of HIVAN and the APOL1 risk variants among HIV-infected individuals of Ethiopian ancestry support a Western rather than Pan-African ancestry risk for ESKD, and can readily explain the lack of HIVAN among individuals of Ethiopian ancestry.