Focal segmental glomerulosclerosis (FSGS) is not a disease, rather a pattern of histological injury occurring from a variety of causes. The exact pathogenesis has yet to be fully elucidated but is ...likely varied based on the type of injury and the primary target of that injury. However, the approach to treatment is often based on the degree of podocyte foot process effacement and clinical presentation without sufficient attention paid to etiology. In this regard, there are many monogenic causes of FSGS with variable presentation from nephrotic syndrome with histological features of primary podocytopathy to more modest degrees of proteinuria with limited evidence of podocyte foot process injury. It is likely that genetic causes are largely underdiagnosed, as the role and the timing of genetic testing in FSGS is not established and genetic counseling, testing options, and interpretation of genotype in the context of phenotype may be outside the scope of practice for both nephrologists and geneticists. Yet most clinicians believe that a genetic diagnosis can lead to targeted therapy, limit the use of high‐dose corticosteroids as a therapeutic trial, and allow the prediction of the natural history and risk for recurrence in the transplanted kidney. In this manuscript, we emphasize that genetic FSGS is not monolithic in its presentation, opine on the importance of genetic testing and provide an algorithmic approach to deployment of genetic testing in a timely fashion when faced with a patient with FSGS.
Elevated serum creatinine at the time of heart transplant is an independent predictor of posttransplant end-stage renal disease (ESRD) and mortality. Patients who are at risk of ESRD should be ...identified before transplantation. We looked at the severity of CKD at the time of waitlisting on posttransplant ESRD and mortality.
We analyzed the United Network of Organ Sharing transplant database from 2000 to 2017. Adults receiving their first heart transplant, and not on dialysis, were included in study. We divided our cohort into 4 groups based on their listing estimated glomerular filtration (eGFR) as well as based on their eGFR at the time of transplant. Primary outcome was all cause mortality and secondary outcome was ESRD.
Compared with the patients on waitlist eGFR ≥60 mL/min/1.73 m, the adjusted subdistribution hazard for ESRD was 1.41 (confidence interval CI, 1.2-1.5), 2.15 (CI, 1.9-2.4), and 2.91 (CI, 2.4-3.5) in the patient groups with eGFR of 45-59, 30-44, and <30 mL/min/1.73 m, respectively. Despite the highest risk of ESRD with the lowest baseline eGFR group, there was a substantial increase in eGFR seen during follow-up with a mean gain of 11 mL/min by year 15 compared with a mean loss of 10 mL/min in the highest eGFR group. Compared with the patients on waitlist eGFR ≥60 mL/min/1.73m, the adjusted hazard ratio for mortality was 1.04 (0.98-1.11), 1.07 (1.00-1.15), and 1.04 (0.91-1.19) in the patient groups with eGFR of 45-59, 30-44, and <30 mL/min/1.73m, respectively.
Our findings show that risk of ESRD post-heart transplant increases with worsening eGFR at waitlisting even after adjusting for multiple confounders.
Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy caused by uncontrolled activation of the alternative pathway of complement at the cell surface level that leads to ...microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. In approximately one half of affected patients, pathogenic loss-of-function variants in regulators of complement or gain-of-function variants in effectors of complement are identified, clearly implicating complement in aHUS. However, there are strong lines of evidence supporting the presence of additional genetic contributions to this disease. To identify novel aHUS-associated genes, we completed a comprehensive screen of the complement and coagulation pathways in 36 patients with sporadic aHUS using targeted genomic enrichment and massively parallel sequencing. After variant calling, quality control, and hard filtering, we identified 84 reported or novel nonsynonymous variants, 22 of which have been previously associated with disease. Using computational prediction methods, 20 of the remaining 62 variants were predicted to be deleterious. Consistent with published data, nearly one half of these 42 variants (19; 45%) were found in genes implicated in the pathogenesis of aHUS. Several genes in the coagulation pathway were also identified as important in the pathogenesis of aHUS. PLG, in particular, carried more pathogenic variants than any other coagulation gene, including three known plasminogen deficiency mutations and a predicted pathogenic variant. These data suggest that mutation screening in patients with aHUS should be broadened to include genes in the coagulation pathway.
Consensus guidelines advise simultaneous heart kidney transplantation (SHK) in heart candidates with an estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m 2 . We hypothesize that a ...significant fraction of such patients would not need an SHK, even though a graded increase in mortality and end-stage kidney disease (ESKD) would be seen with decrements in eGFR.
United Network of Organ Sharing data for isolated heart transplants between 2000 and 2020 were divided into two groups based on eGFR at transplant (≤20 mL/min/1.73 m 2 and 21-29 mL/min/1.73 m 2 ). The primary outcome was mortality and secondary outcome was ESKD posttransplant. Cox regression and cumulative incidence competing risk methods were used to compare risk of mortality and ESKD.
There was no difference in mortality (adjusted hazard ratio aHR 0.82 95% confidence interval, CI: 0.60-1.11, P = 0.21) or ESKD (aHR 1.01 95% CI: 0.49-2.09, P = 0.96) between the two groups (≤20 versus 21-29). The overall incidence of ESKD for the entire cohort at 1, 5, and 10 y were 1.5%, 9.5%, and 20%.
Although risk of ESKD is highest in heart candidates with an eGFR <30 mL/min/1.73 m 2 , <10% of patients reach ESKD within 5 y' and most will recover significant renal function posttransplant. More refined selection criteria are required to identify candidates for SHK.
Cigarette smoking is implicated in numerous diseases, including emphysema and lung cancer. The clinical expression of lung disease in smokers is not well explained by currently defined variations in ...gene expression or simple differences in smoking exposure. Alveolar macrophages play a critical role in the inflammation and remodeling of the lung parenchyma in smoking-related lung disease. Significant gene expression changes in alveolar macrophages from smokers have been identified. However, the mechanism for these changes remains unknown. One potential mechanism for smoking-altered gene expression is via changes in cytosine methylation in DNA regions proximal to gene-coding sequences. In this study, alveolar macrophage DNA from heavy smokers and never smokers was isolated and methylation status at 25,000 loci determined. We found differential methylation in genes from immune-system and inflammatory pathways. Analysis of matching gene expression data demonstrated a parallel enrichment for changes in immune-system and inflammatory pathways. A significant number of genes with smoking-altered mRNA expression had inverse changes in methylation status. One gene highlighted by this data was the FLT1, and further studies found particular up-regulation of a splice variant encoding a soluble inhibitory form of the receptor. In conclusion, chronic cigarette smoke exposure altered DNA methylation in specific gene promoter regions in human alveolar macrophages.
Parachute science (inequity in research relationships between Global North and South scientists) has known detrimental impacts on Global South researchers in conservation. Using two international ...datasets of English and non‐English‐language studies testing conservation interventions, we compared the continents in which studies were conducted to those in which authors were affiliated. We found that a substantial proportion of English‐language studies conducted in Global South continents were led by researchers affiliated to Global North institutions. Studies in the Global South had relatively few locally affiliated lead authors and a higher percentage of studies with no locally affiliated authors. There were similar but typically less pronounced patterns for non‐English‐language studies. We discuss the potential drivers of these problematic findings and future directions that could help avoid and eliminate unethical parachute conservation science.
Diagnosis of monogenic chronic kidney diseases Armstrong, Margaret E; Thomas, Christie P
Current opinion in nephrology and hypertension,
03/2019, Letnik:
28, Številka:
2
Journal Article
Recenzirano
The purpose of this review is to emphasize that single gene disorders are an important and sometimes unrecognized cause of progressive chronic kidney disease. We provide an overview of the benefits ...of making a genetic diagnosis, the currently available genetic testing methods and examples of diseases illustrating the impact of a genetic diagnosis.
Although there are now a number of monogenic renal diseases, only a few, such as autosomal dominant polycystic kidney disease (ADPKD), are generally diagnosable without genetic testing. Complicating clinical diagnosis is that many diseases that classically have characteristic renal or extrarenal findings, often present with an incomplete or overlapping phenotype that requires additional testing to be uncovered. Advances in sequencing technology and bioinformatic processing now give us the ability to screen the entire human genome or exome or an organ-limited subset of genes quickly and inexpensively permitting the unbiased interrogation of hundreds of genes, thus removing the need for precision in clinical diagnosis prior to testing.
We provide an overview of the principal phenotypes seen in chronic kidney disease with a focus on the cystic diseases and ciliopathies, the glomerular diseases, disorders of renal development and the tubulointerstitial diseases. In each of these phenotypes, we provide a listing of some of the important genes that have been identified to date, a brief discussion of the clinical diagnosis, the role of genetic testing and the differentiation of distinct genetic disorders from acquired and genetic phenocopies.
A Renal Genetics Clinic (RGC) was established to optimize diagnostic testing, facilitate genetic counseling, and direct clinical management.
Retrospective review of patients seen over a two-year ...period in the RGC.
One hundred eleven patients (mean age: 39.9 years) were referred to the RGC: 65 for genetic evaluation, 19 for management of a known genetic disease, and 18 healthy living kidney donors (LKDs) and their 9 related transplant candidates for screening. Forty-three patients underwent genetic testing with a diagnosis in 60% of patients including 9 with Alport syndrome, 7 with autosomal dominant polycystic kidney disease (ADPKD), 2 with genetic focal segmental glomerulosclerosis (FSGS), 2 with PAX2-mediated CAKUT, and 1 each with autosomal recessive polycystic kidney disease (ARPKD), Dent, Frasier, Gordon, Gitelman, and Zellweger syndromes. Four of 18 LKDs were referred only for APOL1 screening. For the remaining 14 LKDs, their transplant candidates were first tested to establish a genetic diagnosis. Five LKDs tested negative for the familial genetic variant, four were positive for their familial variant. In five transplant candidates, a genetic variant could not be identified.
An RGC that includes genetic counseling enhances care of renal patients by improving diagnosis, directing management, affording presymptomatic family focused genetic counseling, and assisting patients and LKDs to make informed decisions.
Summary
Heart transplantation is a viable option for end stage heart disease but long‐term complications such as chronic kidney disease are being increasingly recognized. We sought to investigate the ...effect of change in estimated glomerular filtration rate (eGFR) during the heart transplant waitlist period on post‐transplant mortality and end stage kidney disease (ESKD). We analysed the United Network of Organ Sharing heart transplant database from 2000 to 2017. Multivariable Cox regression with restricted cubic splines and cumulative incidence competing risk (CICR) methods were used to compare the effects of change in eGFR on mortality and ESKD, respectively. A total of 19 412 patients met our inclusion criteria. Mortality increased with increasing loss of eGFR (adjusted hazard ratio increased from 1.02 confidence interval (CI) 1.01–1.04, P = 0.008 for 10% loss to 1.15 (CI 1.06–1.26, P = 0.001) for 50% loss of eGFR. Similarly, risk of ESKD also increased monotonically with increasing loss of renal function subdistribution hazard ratio increased from 1.12 (CI 1.09–1.14, P < 0.001) to 2.0 (CI 1.74–2.3, P < 0.001) as loss of eGFR increased from 10% to 50%. Overall, we found that loss of >10% of eGFR resulted in higher risk of mortality and higher risk of ESKD.
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