Project description:The presence of 2 APOL1 risk variants (G1/G1, G1/G2, or G2/G2) is an important predictor of focal segmental glomerulosclerosis (FSGS) and chronic kidney disease in individuals of African descent. Although recipient APOL1 genotype is not associated with allograft survival, kidneys from deceased African American donors with 2 APOL1 risk variants demonstrate shorter graft survival. We present a series of cases of presumed de novo collapsing FSGS in 5 transplanted kidneys from 3 deceased donors later identified as carrying 2 APOL1 risk alleles, including 2 recipients from the same donor whose kidneys were transplanted in 2 different institutions. Four of these recipients had viremia in the period preceding the diagnosis of collapsing FSGS. Cytomegalovirus and BK virus infection were present in 3 and 1 of our 5 cases, respectively, around the time that collapsing FSGS occurred. We discuss viral infections, including active cytomegalovirus infection, as possible "second hits" that may lead to glomerular injury and allograft failure in these recipients. Further studies to identify additional second hits are necessary to better understand the pathologic mechanisms of donor APOL1-associated kidney disease in the recipient.

| S-EPMC6309648 | biostudies-literature

Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts.

Project description:Collapsing focal segmental glomerulosclerosis (cFSGS) in the native kidney is associated with heavy proteinuria and accelerated renal failure. However, cFSGS in the renal allograft is less well characterized. Here we report clinico-pathologic features and APOL1 donor risk genotypes in 38 patients with de novo post-kidney transplant cFSGS. Recipients were 34% female and 26% African American. Concurrent viral infections and acute vaso-occlusion (including thrombotic microangiopathy, cortical necrosis, atheroembolization, and cardiac arrest with contralateral graft thrombosis) were present in 13% and 29% of recipients, respectively. Notably, 61% of patients had concurrent acute rejection and 47% received grafts from African American donors, of which 53% carried APOL1 high-risk genotypes. These frequencies of acute rejection and grafts from African American donors were significantly higher than in our general transplant population (35% and 16%, respectively). Patients had a median serum creatinine of 5.4 mg/dl, urine protein/creatinine 3.5 g/g, and 18% had nephrotic syndrome. Graft failure occurred in 63% of patients at an average of eighteen months post-index biopsy. By univariate analysis, donor APOL1 high-risk genotypes, post-transplant time, nephrotic syndrome, and chronic histologic changes were associated with inferior graft survival while acute vaso-occlusion was associated with superior graft survival. Donor APOL1 high-risk genotypes independently predicted poor outcome. Compared to native kidney cFSGS, post-transplant cFSGS had more acute vaso-occlusion but less proteinuria. Thus, de novo cFSGS is associated with variable proteinuria and poor prognosis with potential predisposing factors of African American donor, acute rejection, viral infection and acute vaso-occlusion. Additionally, donor APOL1 high-risk genotypes are associated with higher incidence and worse graft survival.

| S-EPMC6251748 | biostudies-literature

Project description: Not available

| S-EPMC7865108 | biostudies-literature

Digital spatial profiling of collapsing glomerulopathy.

Project description:Collapsing glomerulopathy is a histologically distinct variant of focal and segmental glomerulosclerosis that presents with heavy proteinuria and portends a poor prognosis. Collapsing glomerulopathy can be triggered by viral infections such as HIV or SARS-CoV-2. Transcriptional profiling of collapsing glomerulopathy lesions is difficult since only a few glomeruli may exhibit this histology within a kidney biopsy and the mechanisms driving this heterogeneity are unknown. Therefore, we used recently developed digital spatial profiling (DSP) technology which permits quantification of mRNA at the level of individual glomeruli. Using DSP, we profiled 1,852 transcripts in glomeruli isolated from formalin fixed paraffin embedded sections from HIV or SARS-CoV-2-infected patients with biopsy-confirmed collapsing glomerulopathy and used normal biopsy sections as controls. Even though glomeruli with collapsing features appeared histologically similar across both groups of patients by light microscopy, the increased resolution of DSP uncovered intra- and inter-patient heterogeneity in glomerular transcriptional profiles that were missed in early laser capture microdissection studies of pooled glomeruli. Focused validation using immunohistochemistry and RNA in situ hybridization showed good concordance with DSP results. Thus, DSP represents a powerful method to dissect transcriptional programs of pathologically discernible kidney lesions.

| S-EPMC9038707 | biostudies-literature

Human apolipoprotein L1 (ApoL1) in cancer and chronic kidney disease.

Project description:Human apolipoprotein L1 (ApoL1) possesses both extra- and intra-cellular functions crucial in host defense and cellular homeostatic mechanisms. Alterations in ApoL1 function due to genetic, environmental, and lifestyle factors have been associated with African sleeping sickness, atherosclerosis, lipid disorders, obesity, schizophrenia, cancer, and chronic kidney disease (CKD). Importantly, two alleles of APOL1 carrying three coding-sequence variants have been linked to CKD, particularly in Sub-Saharan Africans and African Americans. Intracellularly, elevated ApoL1 can induce autophagy and autophagy-associated cell death, which may be critical in the maintenance of cellular homeostasis in the kidney. Similarly, ApoL1 may protect kidney cells against renal cell carcinoma (RCC). We summarize the role of ApoL1 in RCC and CKD, highlighting the critical function of ApoL1 in autophagy.

| S-EPMC3349435 | biostudies-literature

Collapsing Glomerulopathy Associated With Hydrophilic Polymer Emboli.

Project description: Not available

| S-EPMC6451082 | biostudies-literature

The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans.

Project description:Mapping by admixture linkage disequilibrium (LD) detected strong association between nonmuscle myosin heavy chain 9 gene (MYH9) variants on chromosome 22 and nondiabetic nephropathy in African Americans. MYH9-related variants were posited to be the probable, but not necessarily the definitive, causal variants as a result of impressive statistical evidence of association, renal expression, and a role in autosomal dominant MYH9 disorders characterized by progressive glomerulosclerosis (Epstein and Fechtner syndromes). Dense mapping within MYH9 revealed striking LD patterns and racial variation in risk allele frequencies, suggesting population genetic factors such as selection may be operative in this region. Genovese and colleagues examined large chromosomal regions adjacent to MYH9 using genome-wide association methods and non-HapMap single nucleotide polymorphisms identified in Yoruba from the 1000 Genomes project. Statistically stronger associations were detected between two independent sequence variants in the Apolipoprotein L1 gene (APOL1) and nondiabetic nephropathy in African Americans, with odds ratios of 10.5 in idiopathic FSGS and 7.3 in hypertension-attributed ESRD. These kidney disease risk variants likely rose to high frequency in Africa because they confer resistance to trypanosomal infection and protect from African sleeping sickness. Risk variants in MYH9 and APOL1 are in strong LD, and the genetic risk that was previously attributed to MYH9 may reside, in part or in whole, in APOL1, although more complex models of risk cannot be excluded. This association likely explains racial disparities in nondiabetic nephropathy as a result of the high prevalence of risk alleles in individuals of African ancestry.

| S-EPMC7391383 | biostudies-literature

Apolipoprotein L1 (APOL1) risk variant toxicity depends on the haplotype background.

Project description:The Apolipoprotein L1 (APOL1) risk variants G1 and G2 are associated with high rates of kidney disease in African Americans in genetic studies. However, our understanding of APOL1 biology has lagged far behind. Here we report that engineering G1 and G2 mutations on unnatural haplotype backgrounds instead of on the specific G1 and G2 haplotype backgrounds that occur in nature profoundly alters APOL1-mediated cytotoxicity in experimental systems. Thus, in addition to helping resolve some important controversies in the APOL1 field, our demonstration of the critical influence of haplotype background may apply more generally to the study of other genetic variants that cause or predispose to human disease.

| S-EPMC6907738 | biostudies-literature

COVID-19-Associated Collapsing Glomerulopathy: An Emerging Entity.

Project description: Not available

| S-EPMC7196556 | biostudies-literature