Defining Hemodynamic Significance of Renal Artery Stenosis: Insights From a Porcine Model of Graded Renal Artery Stenosis.

RATIONALE AND OBJECTIVES: To investigate the renal pressure-flow relationship and its relation to renin release, because the renal perfusion pressure below which renal flow starts to decline and renin secretion is upregulated is unclear. MATERIALS AND METHODS: A porcine model of graded unilateral renal artery stenosis was created. The severity of the stenosis was expressed as the ratio between distal renal pressure (Pd) and aortic pressure (Pa). Pd and renal flow velocity were continuously measured using a combined pressure-flow wire (Combowire®). Hemodynamic measurements and blood sampling for renin, angiotensin and aldosterone were performed in baseline conditions and during progressive balloon inflation in the renal artery leading to Pd decrease per 5% increment. Resistive index (RI) was computed as (1 - (End Diastolic V/Peak Systolic V))*100. RESULTS: For a 5% decrease in renal perfusion pressure (95% of aortic pressure or 5% decrease compared to Pa), peak systolic velocity started to decrease. A significant decrease in average peak flow velocity was observed when distal renal perfusion pressure decreased by 25% and was associated with activation of ipsilateral renin secretion. The RI decreased already for minimal changes in Pd/Pa ratio. CONCLUSION: In an animal model of unilateral graded renal artery stenosis, a 25% decrease in perfusion pressure results in a significant decrease in distal renal flow, causing upregulation of renin secretion.

On the protein content of kidney stones: an explorative study.

OBJECTIVES: Kidney stone formation is complex; urinary protein inhibitors play a major role in natural defense against stone formation. Using attenuated total-reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy of kidney stones, proteins are usually not quantified and often reported as 'organic matrix', for which there is little attention: treatment of urolithiasis is based on the nature of the major organic/inorganic stone compound. Literature no longer regards urinary proteins as innocent bystander, but highlights the role of proteins as urolithiasis modulators. We explored the potential significance of the protein content of kidney stones. METHODS: 800 stones were analyzed using ATR-FTIR spectroscopy; spectra were corrected for protein content. The ratio of the amide I peak (1655 cm-1) divided by the maximum peak was calculated. A subgroup of stones (n = 43) was weighed; protein concentration was assayed. Kidney stone composition was taken into account when calculating protein concentration. Electrophoresis was implemented to investigate the protein bands. Multiple regression analysis was carried out to study the influence of various demographic variables (age, gender, stone type) on protein concentration. RESULTS: Protein concentration showed a marked variation according to the stone composition. High relative protein content (>0.4% stone mass) was found in mixed calcium apatite/calcium oxalate dihydrate stones, mixed calcium oxalate dihydrate/calcium oxalate monohydrate/calcium apatite stones, and mixed calcium oxalate monohydrate/brushite stones, whereas lower protein percentages were found in cystine, urate, and calcium oxalate monohydrate stones. Protein concentration was dependent of the patient's age. CONCLUSION: ATR-FTIR is a practical way for assessing protein concentration in kidney stones. LIST OF ABBREVIATIONS: A: absorbance; as, asymmetric vibrations; ATR-FTIR, attenuated total-reflectance Fourier-transform infrared; ß, standardized regression coefficient; CAP, calcium apatite; COD, calcium oxalate dihydrate; COM, calcium oxalate monohydrate; CV, coefficient of variation; δ, bending vibrations; ELISA, enzyme-linked immunosorbent assay; IQR, interquartile range; IR, infrared; LOD, limit of detection; LOQ, limit of quantification; MIR, mid-infrared; N or n, amount; r, correlation; r2, coefficient of determination; s, symmetric vibrations; SD, standard deviation; SE, standard error; THP, Tamm-Horsfall protein; UA, uric acid; V, stretching vibrations; VIF: variance inflation factor; ZnSe, zinc selenide.

Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases.

Fibromuscular dysplasia (FMD) is an arteriopathy associated with hypertension, stroke and myocardial infarction, affecting mostly women. We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We find an estimate of SNP-based heritability compatible with FMD having a polygenic basis, and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identifies one additional locus (SLC24A3). We characterize open chromatin in arterial primary cells and find that FMD associated variants are located in arterial-specific regulatory elements. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We find significant genetic overlap between FMD and more common cardiovascular diseases and traits including blood pressure, migraine, intracranial aneurysm, and coronary artery disease.

Genetic Polymorphisms in the Host and COVID-19 Infection.

The outbreak of the COVID-19 pandemic shows a marked geographical variation in its prevalence and mortality. The question arises if the host genetic variation may (partly) affect the prevalence and mortality of COVID-19. We postulated that the geographical variation of human polymorphisms might partly explain the variable prevalence of the infection. We investigated some candidate genes that have the potential to play a role in the immune defense against COVID-19: complement component 3 (C3), galactoside 2-alpha-L-fucosyltransferase 2 (FUT2), haptoglobin (Hp), vitamin D binding protein (DBP), human homeostatic iron regulator protein (HFE), cystic fibrosis transmembrane conductance regulator (CFTR), and angiotensin-converting enzyme 1 (ACE1). In a univariate approach, ACE1 D/I, C3, CFTR, and HFE polymorphisms correlated significantly with COVID-19 prevalence/mortality, whereas Hp and FUT2 polymorphism did not show any significant correlations. In a multivariate analysis, only ACE1 D/I and C3 polymorphisms were determinants for COVID-19 prevalence/mortality. The other polymorphisms (CFTR, DBP, FUT2, HFE, and Hp) did not correlate with COVID-19 prevalence/mortality. Whereas ACE1 D/I polymorphism shows functional links with ACE2 (which is the receptor for the virus) in COVID-19, C3 can act as a critical step in the virus-induced inflammation. Our findings plead against a bystander role of the polymorphisms as a marker for historical migrations, which comigrate with causal genes involved in COVID-19 infection. Further studies are required to assess the clinical outcome of COVID-19 in C3S and ACE1 D allele carriers and to study the role of C3 and ACE1 D/I polymorphisms in COVID-19 and their potential effects on treatment response.

Sex differences in the association between arterial hypertension, blood pressure, and sleep apnea in the general population.

STUDY OBJECTIVES: To assess sex-related differences in the relationship between hypertension (HT), blood pressure (BP), and sleep apnea in the general population. METHODS: We performed home polygraphy in a cohort of 1809 men and women in the general population. Office BP was measured. Presence of HT (drug-treated, physician-diagnosed, or high BP during study visit) was also recorded. HT rate and BP were assessed over a range of 7 sleep apnea severity categories based on the respiratory event index (REI). RESULTS: The age-adjusted HT prevalence rate increased with higher REI in both sexes. After additional adjustment for obesity the association remained significant in women but not in men. In participants not treated with antihypertensive medications, age-adjusted BP increased with REI. Remarkably, the association was already significant within the normal range (REI < 5 events/h). The REI threshold for higher BP was situated at a distinctly lower cutoff point in women compared to men. After additional adjustment for obesity, the associations remained significant for diastolic but not systolic BP. CONCLUSIONS: Significant increases in the age-adjusted BP and HT rate in the general population were present at lower REI cutoffs in women compared to men. Even a very low number of respiratory events was associated with higher BP and HT prevalence. Adjustment for obesity attenuated these associations, especially in men. Sex differences in BP susceptibility across the sleep apnea spectrum may be present.

Longitudinal Changes of Input Impedance, Pulse Wave Velocity, and Wave Reflection in a Middle-Aged Population: The Asklepios Study.

[Figure: see text].