Kidney disease-associated variants of Apolipoprotein L1 show gain-of-function in cation channel activity

Variants in Apolipoprotein L1 (ApoL1) are known to be responsible for increased risk of some progressive kidney diseases among people of African ancestry. ApoL1 is an amphitropic protein that can insert into phospholipid membranes and confer anion- or cation-selective permeability to phospholipid membranes depending on pH. Whether these activities differ among the variants or whether they contribute to disease pathogenesis is unknown. We used assays of voltage-driven ion flux from phospholipid vesicles and of stable membrane association to assess differences among ApoL1 isoforms. There is a significant (approximately two-fold) increase in the cation-selective ion permease activity of the two kidney-disease-associated variants compared to the reference protein. In contrast, we find no difference in the anion-selective permease activity at low pH among the isoforms. Compared with the reference sequence, the two disease-associated variants show increased stable association with phospholipid vesicles under conditions that support the cation permease activity, suggesting that the increased activity may be due to more efficient membrane association and insertion. There is no difference in membrane association among isoforms under optimal conditions for the anion permease activity. These data support a model in which enhanced cation permeability may contribute to the progressive kidney diseases associated with high-risk ApoL1 alleles.

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Stroke in chronic renal failure

Orvosi Hetilap ◽

10.1556/oh.2008.28292 ◽

2008 ◽

Vol 149 (15) ◽

pp. 691-696

Author(s):

Dániel Bereczki

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Disease ◽

Chronic Renal Disease ◽

Kidney Diseases ◽

Cerebrovascular Diseases ◽

Lipid Lowering ◽

Increased Risk ◽

Intracerebral Hemorrhages

Chronic kidney diseases and cardiovascular diseases have several common risk factors like hypertension and diabetes. In chronic renal disease stroke risk is several times higher than in the average population. The combination of classical risk factors and those characteristic of chronic kidney disease might explain this increased risk. Among acute cerebrovascular diseases intracerebral hemorrhages are more frequent than in those with normal kidney function. The outcome of stroke is worse in chronic kidney disease. The treatment of stroke (thrombolysis, antiplatelet and anticoagulant treatment, statins, etc.) is an area of clinical research in this patient group. There are no reliable data on the application of thrombolysis in acute stroke in patients with chronic renal disease. Aspirin might be administered. Carefulness, individual considerations and lower doses might be appropriate when using other treatments. The condition of the kidney as well as other associated diseases should be considered during administration of antihypertensive and lipid lowering medications.

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Climate Change and the Kidney

Annals of Nutrition and Metabolism ◽

10.1159/000500344 ◽

2019 ◽

Vol 74 (Suppl. 3) ◽

pp. 38-44 ◽

Cited By ~ 14

Author(s):

Richard J. Johnson ◽

Laura G. Sánchez-Lozada ◽

Lee S. Newman ◽

Miguel A. Lanaspa ◽

Henry F. Diaz ◽

...

Keyword(s):

Heat Stress ◽

Kidney Disease ◽

Heat Waves ◽

Kidney Diseases ◽

Whole Body ◽

Increased Risk ◽

Adequate Hydration ◽

Acute Kidney Disease ◽

Heat Extremes ◽

Tract Infections

The worldwide increase in temperature has resulted in a marked increase in heat waves (heat extremes) that carries a markedly increased risk for morbidity and mortality. The kidney has a unique role not only in protecting the host from heat and dehydration but also is an important site of heat-associated disease. Here we review the potential impact of global warming and heat extremes on kidney diseases. High temperatures can result in increased core temperatures, dehydration, and blood hyperosmolality. Heatstroke (both clinical and subclinical whole-body hyperthermia) may have a major role in causing both acute kidney disease, leading to increased risk of acute kidney injury from rhabdomyolysis, or heat-induced inflammatory injury to the kidney. Recurrent heat and dehydration can result in chronic kidney disease (CKD) in animals and theoretically plays a role in epidemics of CKD developing in hot regions of the world where workers are exposed to extreme heat. Heat stress and dehydration also has a role in kidney stone formation, and poor hydration habits may increase the risk for recurrent urinary tract infections. The resultant social and economic consequences include disability and loss of productivity and employment. Given the rise in world temperatures, there is a major need to better understand how heat stress can induce kidney disease, how best to provide adequate hydration, and ways to reduce the negative effects of chronic heat exposure.

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Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study

10.1101/2021.09.29.21264100 ◽

2021 ◽

Author(s):

Bernt Popp ◽

Arif B. Ekici ◽

Karl X. Knaup ◽

Karen Schneider ◽

Steffen Uebe ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Kidney Diseases ◽

Diagnostic Yield ◽

Genetic Disorder ◽

Clinical Criteria ◽

Pathogenic Variants ◽

Increased Risk ◽

Monogenic Diseases ◽

Disease Study

ABSTRACTExome sequencing (ES) studies in chronic kidney disease (CKD) cohorts could identify pathogenic variants in ∼10% of patients. This implies underdiagnosis of hereditary CKD. Tubulointerstitial kidney diseases, showing no typical clinical/histologic finding but tubulointerstitial fibrosis, are particularly difficult to diagnose.We used a custom designed targeted panel (29 genes) and MUC1-SNaPshot to sequence 271 DNA samples, selected by clinical criteria from 5,217 individuals in the German Chronic Kidney Disease (GCKD) cohort.We identified 33 pathogenic small variants. Of these 27 (81.8%) were in COL4-genes, the largest group being 15 COL4A5-variants with nine unrelated individuals carrying c.1871G>A, p.(Gly624Asp). We found three cysteine variants in UMOD, a novel missense, and a novel splice variant in HNF1B and the homoplastic MTTF variant m.616T>C. Copy-number analysis identified a heterozygous COL4A5-deletion, and a HNF1B-duplication/-deletion, respectively. Overall, pathogenic variants were present in 12.5% (34/271) and variants of unknown significance in 9.6% (26/271) of selected individuals. Bioinformatic predictions paired with gold standard diagnostics for MUC1 (SNaPshot) could not identify the typical cytosine duplication (“c.428dupC”) in any individual, implying that ADTKD-MUC1 is rare.Our study shows that >10% of individuals with certain clinical features carry disease variants in genes associated with tubulointerstitial kidney diseases. COL4-genes constitute the largest fraction, implying they are overlooked using clinical Alport-syndrome criteria. We also identified variants easily missed by some ES pipelines. Finally, our results indicate that the filtering criteria applied enrich for an underlying genetic disorder.SIGNIFICANCE STATEMENTCKD affects >10% of the global population and recent studies imply that a considerable portion can be attributed to monogenic diseases, which are likely underappreciated in the clinical routine. Tubulointerstitial kidney diseases are a particularly difficult group of hereditary kidney diseases to diagnose both clinically and genetically. To investigate the prevalence of these disorders in a large CKD cohort we established a set of clinical criteria and designed a custom panel sequencing pipeline. Based on the diagnostic yield of 12.5%, we recommend an algorithm to clinically select and genetically evaluate patients with increased risk for a hereditary tubulointerstitial kidney disease.

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End-Stage Kidney Diseases in Immigrant Groups: A Nationwide Cohort Study in Sweden

American Journal of Nephrology ◽

10.1159/000497063 ◽

2019 ◽

Vol 49 (3) ◽

pp. 186-192 ◽

Cited By ~ 1

Author(s):

Per Wändell ◽

Axel C. Carlsson ◽

Xinjun Li ◽

Danijela Gasevic ◽

Johan Ärnlöv ◽

...

Keyword(s):

Cohort Study ◽

Kidney Disease ◽

Second Generation ◽

Cox Regression ◽

Kidney Diseases ◽

Incidence Rates ◽

Foreign Born ◽

Second Generation Immigrants ◽

Increased Risk ◽

End Stage

Background: Our aim was to study the association between the country of birth and incident end-stage kidney disease (ESKD) in several immigrant groups in Sweden, using individuals born in Sweden or with Swedish-born parents as referents. Methods: A cohort study of first- and second-generation immigrants residing in Sweden between January 1, 1998 and December 31, 2012 was performed. Outcomes were defined as having at least one registered diagnosis of ESKD in the National Patient Register. The incidence of ESKD in different immigrant groups was used in the Cox regression models to estimate hazard ratios (HRs) and 95% CIs. All models were stratified by sex and adjusted for age, geographical residence, educational level, marital status, and neighbourhood socioeconomic status. Results: Compared to their referents, higher incidence rates and HRs of ESKD (HR; 95% CI) were observed in general among foreign-born men (1.10; 1.04–1.16) and women (1.12; 1.04–1.21) but not among second-generation immigrants (persons born in Sweden with foreign-born parents). A particularly high incidence was noted among men and women from East-European countries, as well as from non-European regions. A lower incidence of ESKD was noted among men from Finland. Conclusions: We observed substantial differences in incidence of ESKD between immigrant groups and the Swedish-born population, which may be clinically relevant when monitoring preventive measures in patient subgroups with a higher risk of deteriorating kidney disease, and suggest higher attention to hypertension and diabetes control in immigrants. Mechanisms attributable to the migration process or ethnic differences may lead to an increased risk of ESKD.

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Gene of the month: APOL1

Journal of Clinical Pathology ◽

10.1136/jclinpath-2020-206517 ◽

2020 ◽

Vol 73 (8) ◽

pp. 441-443

Author(s):

Shanel Raghubeer ◽

Tahir S Pillay ◽

Tandi Edith Matsha

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

African Ancestry ◽

Structure And Function ◽

Trypanosome Infection ◽

Systemic Lupus ◽

Disease Outcomes ◽

Increased Risk ◽

And Function ◽

Apolipoprotein L1

Apolipoprotein L1 (APOL1) is a protein encoded by the APOL1 gene, found only in humans and several primates. Two variants encoding two different isoforms exist for APOL1, namely G1 and G2. These variants confer increased protection against trypanosome infection, and subsequent African sleeping sickness, and also increase the likelihood of renal disease in individuals of African ancestry. APOL1 mutations are associated with increased risk of chronic kidney disease, inflammation, and exacerbation of systemic lupus erythematosus-associated renal dysfunction. This review serves to outline the structure and function of APOL1, as well as its role in several disease outcomes.

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UBD modifies APOL1-induced kidney disease risk

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1716113115 ◽

2018 ◽

Vol 115 (13) ◽

pp. 3446-3451 ◽

Cited By ~ 22

Author(s):

Jia-Yue Zhang ◽

Minxian Wang ◽

Lei Tian ◽

Giulio Genovese ◽

Paul Yan ◽

...

Keyword(s):

Kidney Disease ◽

Disease Risk ◽

African Ancestry ◽

Genetic Modifiers ◽

Cell Toxicity ◽

Mapping Study ◽

Risk Alleles ◽

Inflammatory Stimuli ◽

Coding Variants ◽

Apolipoprotein L1

People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk APOL1 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with APOL1. We performed an admixture mapping study to identify genetic modifiers of APOL1-associated kidney disease. Individuals with two APOL1 risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the UBD (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the UBD locus correlates with lower levels of UBD expression. In cell-based experiments, the disease-associated APOL1 alleles (known as G1 and G2) lead to increased abundance of UBD mRNA but to decreased levels of UBD protein. UBD gene expression inversely correlates with G1 and G2 APOL1-mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both UBD and APOL1, which interact in a functionally important manner. UBD appears to mitigate APOL1-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in UBD and UBD expression appear to modify the APOL1-associated kidney phenotype.

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One size does not fit all: understanding individual living kidney donor risk

Pediatric Nephrology ◽

10.1007/s00467-019-04456-8 ◽

2020 ◽

Cited By ~ 1

Author(s):

Elham Asgari ◽

Rachel M. Hilton

Keyword(s):

Gestational Hypertension ◽

African Ancestry ◽

Individual Risk ◽

Living Kidney Donor ◽

Increased Risk ◽

Transplant Candidates ◽

End Stage ◽

Donor Consent ◽

Apolipoprotein L1 ◽

Donor Kidney Transplantation

AbstractLiving donor kidney transplantation is the optimal treatment for end-stage kidney disease (ESKD) but confers a risk upon the donor, both in the short term and many years after donation. While perioperative mortality is low and longevity does not appear to be adversely affected, there are small increases in the risk of other important morbidities. The overall risk of ESKD among donors is low but appears to be three- to five-fold higher than among healthy non-donors, and this relative risk is even higher among donors of African ancestry. For these individuals, apolipoprotein L1 genotyping may be helpful. Kidney donors also have an increased risk of developing hypertension post-donation and a modestly increased risk of developing gout. Living kidney donation also increases the risk of gestational hypertension and preeclampsia while not affecting other important pregnancy outcomes. As our understanding of donor risk grows, it is important to counsel prospective donors according to their individual risk and so obtain better informed donor consent. As knowledge advances, it is also important that all clinicians who manage kidney transplant candidates have an up to date understanding of donor risk to inform shared decision making.

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Prognosis of COVID-19 in Patients with Liver and Kidney Diseases: An Early Systematic Review and Meta-Analysis

Tropical Medicine and Infectious Disease ◽

10.3390/tropicalmed5020080 ◽

2020 ◽

Vol 5 (2) ◽

pp. 80 ◽

Cited By ~ 21

Author(s):

Tope Oyelade ◽

Jaber Alqahtani ◽

Gabriele Canciani

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Liver Diseases ◽

Case Fatality Rate ◽

Kidney Diseases ◽

Meta Analysis ◽

Case Fatality ◽

Preventative Measures ◽

Increased Risk ◽

Liver And Kidney

The mortality and severity in COVID-19 is increased in patients with comorbidities. The aim of this study was to evaluate the severity and mortality in COVID-19 patients with underlying kidney and liver diseases. We retrieved data on the clinical features and primary composite end point of COVID-19 patients from Medline and Embase which had been released from inception by the April 16, 2020. The data on two comorbidities, liver diseases and chronic kidney disease, were pooled and statistically analysed to explain the associated severity and mortality rate. One hundred and forty-two abstracts were screened, and 41 full articles were then read. In total, 22 studies including 5595 COVID-19 patients were included in this study with case fatality rate of 16%. The prevalence of liver diseases and chronic kidney disease (CKD) were 3% (95% CI; 2–3%) and 1% (95% CI; 1–2%), respectively. In patients with COVID-19 and underlying liver diseases, 57.33% (43/75) of cases were severe, with 17.65% mortality, while in CKD patients, 83.93% (47/56) of cases were severe and 53.33% (8/15) mortality was reported. This study found an increased risk of severity and mortality in COVID-19 patients with liver diseases or CKD. This will lead to better clinical management and inform the process of implementing more stringent preventative measures for this group of patients.

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An ordered sequential mechanism for Factor IX and Factor IXa binding to platelet receptors in the assembly of the Factor X-activating complex

Biochemical Journal ◽

10.1042/bj20050029 ◽

2005 ◽

Vol 390 (1) ◽

pp. 157-167 ◽

Cited By ~ 6

Author(s):

Xia Yang ◽

Peter N. Walsh

Keyword(s):

Fold Increase ◽

Factor Ix ◽

Phospholipid Vesicles ◽

Phospholipid Membranes ◽

Factor X ◽

Wild Type ◽

Binding Assays ◽

Epidermal Growth Factor Domain ◽

Factor Ixa ◽

Activated Platelets

To define the contributions of the Ω-loop of the Gla (γ-carboxyglutamic acid) domain and the EGF2 (second epidermal growth factor) domain of FIXa (Factor IXa) in the assembly of the FX-activating complex on activated platelets and phospholipid membranes, three recombinant FIXa chimeras were prepared with corresponding residues from the homologous coagulation protein, FVII: (i) Gly4–Gln11 (FIXa7Ωloop), (ii) Cys88–Cys124 (FIXa7EGF2), and (iii) both Gly4–Gln11 and Cys88–Cys124 (FIXa7Ωloop7EGF2). All three chimeras were similar to wild-type FIXa, as assessed by SDS/PAGE, active-site titration, content of Gla residues, activation rates by FXIa and rates of FXa generation in solution. Titrations of FX or FVIIIa on SFLLRN peptide-activated platelets and on phospholipid vesicles in the presence of FVIIIa revealed normal substrate and cofactor binding to all chimeras. In kinetic assays in the presence of phospholipid vesicles and FVIIIa, compared with wild-type FIXa Kd, app∼4 nM, the FIX7Ωloop chimera showed a 1.6-fold increase in Kd, app, the FIX7EGF2 chimera had a 7.4-fold increase in Kd, app, and the FIX7Ωloop7EGF2 chimera showed a 21-fold increase in Kd, app. In kinetic assays and equilibrium platelet-binding assays with activated platelets and FVIIIa, compared with wild-type FIXa (Vmax∼5 nM min−1; Kd, app∼0.5 nM; Bmax∼550 sites/platelet; Kd∼0.5 nM), the FIX7Ωloop chimera displayed 2-fold decreases in Vmax and Bmax and 2-fold increases in Kd, app and Kd. The FIX7EGF2 chimera displayed 2-fold decreases in Vmax and Bmax and 10-fold increases in Kd, app and Kd. The FIX7Ωloop7EGF2 chimera showed non-saturable curves and severely impaired rates of FXa generation, and non-saturable, non-specific, low-level binding to activated platelets. Thus both the Gla domain Ω-loop (Gly4–Gln11) and the EGF2 domain (Cys88–Cys124) are required to mediate the normal assembly of the FX-activating complex on activated platelets and on phospholipid membranes.

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HIV Viremia Is Associated With APOL1 Variants and Reduced JC-Viruria

Frontiers in Medicine ◽

10.3389/fmed.2021.718300 ◽

2021 ◽

Vol 8 ◽

Author(s):

Etty Kruzel-Davila ◽

Barbara Mensah Sankofi ◽

Ernestine Kubi Amos-Abanyie ◽

Anita Ghansah ◽

Alexander Nyarko ◽

...

Keyword(s):

Kidney Disease ◽

Jc Virus ◽

African Ancestry ◽

Research Network ◽

Risk Alleles ◽

Immune System Activation ◽

Increased Risk ◽

Persons Living With Hiv ◽

Living With Hiv

Variants in the Apolipoprotein L1 (APOL1) gene (G1-rs60910145, rs73885319, G2-rs71785313) are common in Africans and in individuals of recent African ancestry and are associated with an increased risk of non-diabetic chronic kidney disease (CKD) and in particular of HIV associated nephropathy (HIVAN). In light of the significantly increased risk of HIVAN in carriers of two APOL1 risk alleles, a role in HIV infectivity has been postulated in the mechanism of APOL1 associated kidney disease. Herein, we aim to explore the association between HIV viremia and APOL1 genotype. In addition, we investigated interaction between BK and JC viruria, CKD and HIV viremia. A total of 199 persons living with HIV/AIDS (comprising 82 CKD cases and 117 controls) from among the participants in the ongoing Human Heredity and Health in Africa (H3Africa) Kidney Disease Research Network case control study have been recruited. The two APOL1 renal risk alleles (RRA) genotypes were associated with a higher risk of CKD (OR 12.6, 95% CI 3.89–40.8, p < 0.0001). Even a single APOL1 RRA was associated with CKD risk (OR 4.42, 95% CI 1.49–13.15, p = 0.007). The 2 APOL1 RRA genotypes were associated with an increased probability of having HIV viremia (OR 2.37 95% CI 1.0–5.63, p = 0.05). HIV viremia was associated with increased CKD risk (OR 7.45, 95% CI 1.66–33.35, P = 0.009) and with a significant reduction of JC virus urine shedding (OR 0.35, 95% CI 0.12–0.98, p = 0.046). In contrast to prior studies, JC viruria was not associated with CKD but was restricted in patients with HIV viremia, regardless of CKD status. These findings suggest a role of APOL1 variants in HIV infectivity and emphasize that JC viruria can serve as biomarker for innate immune system activation.

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