3 research outputs found
ADPKD: Prototype of Cardiorenal Syndrome Type 4
The cardiorenal syndrome type 4 (Chronic Renocardiac Syndrome) is characterized by a condition of primary chronic kidney disease (CKD) that leads to an impairment of the cardiac function, ventricular hypertrophy, diastolic dysfunction, and/or increased risk of adverse cardiovascular events. Clinically, it is very difficult to distinguish between CRS type 2 (Chronic Cardiorenal Syndrome) and CRS type 4 (Chronic Renocardiac Syndrome) because often it is not clear whether the primary cause of the syndrome depends on the heart or the kidney. Autosomal dominant polycystic kidney disease (ADPKD), a genetic disease that causes CKD, could be viewed as an ideal prototype of CRS type 4 because it is certain that the primary cause of cardiorenal syndrome is the kidney disease. In this paper, we will briefly review the epidemiology of ADPKD, conventional and novel biomarkers which may be useful in following the disease process, and prevention and treatment strategies
Red Blood Cell Abnormalities as the Mirror of SARS-CoV-2 Disease Severity: A Pilot Study
PurposeUnraveling the pathophysiology of COVID-19 disease is of crucial
importance for designing treatment. The purpose of this study is to
investigate the effects of the disease on erythrocytes (RBCs) and to
correlate the findings with disease severity. Materials and
MethodsHospitalized patients (n = 36) with COVID-19 and control group of
healthy volunteers (n = 18) were included in the study. Demographic
data, clinical, laboratory and chest Computed Tomography (CT) findings
at time of admission were recorded. Laboratory measurements included:
Hemoglobin (H b), indirect billirubin, LDH, D-Dimers, and plasma free
hemoglobin (plasma free-Hb). On RBCs were performed: osmotic fragility
(MCF), Free-Hb after mechanical stress (Free-Hb-MECH), intracellular RBC
concentration of calcium ions (iCa(2+)), intracellular ROS (iROS), G6PD,
intracellular active caspase-3 (RBC-caspase-3), IgG immunoglobulins
(RBC-IgGs), which are bound on RBCs’ senescent neo-antigen proteins and
RBC surface phosphatidylserine (RBC-PS). ResultsThe percentage of males
was 50 and 66% and the mean age was 65.16 +/- 14.24 and 66.33 +/- 13.48
years among patients and controls respectively (mean +/- SD, p = 0.78).
Upon admission patients’ PO2/FiO(2) ratio was 305.92 +/- 76.75 and
distribution of infiltration extend on chest CT was: 0-25% (N = 19),
25-50%: (N = 7), and 50-75% (N = 9). Elevated hemolysis markers (LDH
and plasma free-Hb) were observed in patients compared to the control
group. Patients’ RBCs were more sensitive to mechanical stress, and
exhibited significantly elevated apoptotic markers (iCa(2+), RBC-PS).
Plasma free Hb levels correlated with the extend of pulmonary
infiltrates on chest CT in COVID-19 patients. Surprisingly, patients’
RBC-iROS were decreased, a finding possibly related with the increased
G6PDH levels in this group, suggesting a possible compensatory mechanism
against the virus. This compensatory mechanism seemed to be attenuated
as pulmonary infiltrates on chest CT deteriorated. Furthermore, RBC-IgGs
correlated with the severity of pulmonary CT imaging features as well as
the abnormality of lung function, which are both associated with
increased disease severity. Lastly, patients’ D-Dimers correlated with
RBC surface phosphatidylserine, implying a possible contribution of the
red blood cells in the thrombotic diathesis associated with the
SARS-CoV-2 disease. ConclusionThis pilot study suggests that SARS-CoV-2
infection has an effect on red blood cells and there seems to be an
association between RBC markers and disease severity in these patients
Association of Rare CYP39A1 Variants with Exfoliation Syndrome Involving the Anterior Chamber of the Eye
IMPORTANCE: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. OBJECTIVE: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. DESIGN, SETTING, AND PARTICIPANTS: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. EXPOSURES: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. MAIN OUTCOMES AND MEASURES: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10(−6). The secondary outcomes included biochemical enzymatic assays and gene expression analyses. RESULTS: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10(−7)). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. CONCLUSIONS AND RELEVANCE: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings