Urinary Kininogen-1 and Retinol binding protein-4 respond to Acute Kidney Injury: Predictors of patient prognosis?

Implementation of therapy for acute kidney injury (AKI) depends on successful prediction of individual patient prognosis. Clinical markers as serum creatinine (sCr) have limitations in sensitivity and early response. The aim of the study was to identify novel molecules in urine which show altered levels in response to AKI and investigate their value as predictors of recovery. Changes in the urinary proteome were here investigated in a cohort of 88 subjects (55 AKI patients and 33 healthy donors) grouped in discovery and validation independent cohorts. Patients'urine was collected at three time points: within the first 48 h after diagnosis(T1), at 7 days of follow-up(T2) and at discharge of Nephrology(T3). Differential gel electrophoresis was performed and data were confirmed by Western blot (WB), liquid chromatography/mass spectrometry (LC-MS/MS) and enzyme-linked immunosorbent assay (ELISA). Retinol binding protein 4 (RBP4) and kininogen-1 (KNG1) were found significantly altered following AKI. RBP4 increased at T1, and progressively decreased towards normalization. Maintained decrease was observed for KNG1 from T1. Individual patient response along time revealed RBP4 responds to recovery earlier than sCr. In conclusion, KNG1 and RBP4 respond to AKI. By monitoring RBP4, patient's recovery can be anticipated pointing to a role of RBP4 in prognosis evaluation.Funding: from Instituto de Salud Carlos III: FIS PI11/01401, PI13/01873, FIS IF08/3667-1, CP09/00229, PI13/00047, PI10/00624, ISCIII-RETIC REDinREN RD012/0021. FEDER funds, Comunidad de Madrid/CIFRA S2010/BMD-2378, Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to AO, IDCSalud (3371/002) and Fundación Conchita Rábago de Jiménez Díaz, Proteomic Facility from Universidad Complutense de Madrid-Fundación Parque Científico de Madrid (UCM-FPCM), Spain, a member of ProteoRed-ISCIII Network member of ProteoRed- ISCIII Networ

Vasoconstriction of the afferent arteriole and defective renal synthesis of nitric oxide in essential hypertension

This study was designed to investigate whether some relation exists between afferent arteriolar resistance (AAR) and the renal production of nitric oxide (NO) and prostacyclin (PGI2) in 21 patients with untreated essential hypertension and 20 normotensive controls. All subjects were studied in conditions of an unlimited Na+ diet both basally and after a four-hour amino acid infusion. AAR was calculated using Gomez's equations. Renal production of NO and PGI2 were assessed by radioimmunoassay of the urinary excretion of cGMP and 6-keto-PGF1 alpha, respectively. Baseline AAR was higher (P < 0.01) in hypertensives than in normotensives. The baseline urinary excretion of 6-keto-PGF1 alpha and cGMP were similar in the two groups of subjects. AAR diminished (P < 0.005) in normotensives and remained unchanged in hypertensives after amino acid infusion. Urinary excretion of 6-keto-PGF1 alpha was increased similarly in the two groups of subjects after infusion. Urinary excretion of cGMP remained unchanged in normotensives and decreased by 31% in hypertensives after infusion. These findings suggest that afferent vasoconstriction present in hypertensive patients is unresponsive to the vasodilatory manoeuvre of amino acid infusion. This lack of response may be due to a defective renal synthesis of NO in these patients

Vasoconstriction of the afferent arteriole and defective renal synthesis of nitric oxide in essential hypertension

This study was designed to investigate whether some relation exists between afferent arteriolar resistance (AAR) and the renal production of nitric oxide (NO) and prostacyclin (PGI2) in 21 patients with untreated essential hypertension and 20 normotensive controls. All subjects were studied in conditions of an unlimited Na+ diet both basally and after a four-hour amino acid infusion. AAR was calculated using Gomez's equations. Renal production of NO and PGI2 were assessed by radioimmunoassay of the urinary excretion of cGMP and 6-keto-PGF1 alpha, respectively. Baseline AAR was higher (P < 0.01) in hypertensives than in normotensives. The baseline urinary excretion of 6-keto-PGF1 alpha and cGMP were similar in the two groups of subjects. AAR diminished (P < 0.005) in normotensives and remained unchanged in hypertensives after amino acid infusion. Urinary excretion of 6-keto-PGF1 alpha was increased similarly in the two groups of subjects after infusion. Urinary excretion of cGMP remained unchanged in normotensives and decreased by 31% in hypertensives after infusion. These findings suggest that afferent vasoconstriction present in hypertensive patients is unresponsive to the vasodilatory manoeuvre of amino acid infusion. This lack of response may be due to a defective renal synthesis of NO in these patients

Association of increased erythrocyte Na+/H+ exchanger with renal Na+ retention in patients with essential hypertension

The goal of this study was to investigate the activity of the Na+/H+ exchanger in erythrocytes of patients with essential hypertension and its relation with urinary Na+ excretion. The study was performed in cells from 27 untreated hypertensive patients and 30 normotensive controls with similar age and sex distribution. All subjects were studied after 4 days on a controlled Na+ diet (145 mmol/day). The activity of the Na+/H+ exchanger was determined by acidifying cell pH and measuring the initial rate of the net Na(+)-dependent H+ efflux. The activity of the Na+/H+ exchanger was higher in hypertensive patients than in controls (301 +/- 45 v 162 +/- 23 mmol/L cells/h, mean +/- SEM; P < .01). With the upper limit of the normotensive population as a cut-off point (385 mmol/L cells/h), a subgroup of 12 hypertensive patients had an abnormally high activity of Na+/H+ exchanger. Compared with controls and with patients with normal exchanger activity, patients with increased exchanger activity were characterized by lower net (P < .01) and fractional (P < .05) Na+ excretion. The accumulative Na+ balance was higher (P < .01) in hypertensive patients with increased activity of the exchanger (39.90 +/- 3.47 mmol) than in the remaining hypertensive patients (0.59 +/- 6.96 mmol) or in the normotensive population (-5.71 +/- 6.12 mmol). After analyzing the relationship of renin activity with Na+ excretion it was observed that renin activity was inappropriately low in 9 (75%) patients with increased exchanger, in 6 (40%) patients with normal exchanger, and in 6 (20%) normotensives, these differences being significant (P<.01)

Decreased excretion of nitrate and nitrite in essential hypertensives with renal vasoconstriction

Most hypertensive patients exhibit increased renal vascular resistance (RVR). This study was designed to investigate whether there exists any relationship between RVR and the production of nitric oxide (NO) in patients with essential hypertension. The study was performed in 49 non-treated patients with mild-to-moderate essential hypertension, and 20 age- and sex-matched normotensive subjects on a controlled sodium diet. Renal hemodynamics was measured in terms of the clearance of para-aminohippuric acid and inulin. Urinary excretion of nitrate and nitrite (NO3- plus NO2-) was determined as an index of NO production. As compared with normotensives, hypertensive patients exhibited higher (P < 0.001) RVR and lower (P < 0.05) urinary excretion of NO3- plus NO2-. With the 100% confidence (upper) limit of the normotensive population as a cut-off point, a subgroup of 30 hypertensives had an abnormally high RVR. The excretion of NO3- plus NO2- was lower (P < 0.005) in hypertensives with high RVR than in normotensives and the remaining hypertensives. No differences were found in the urinary excretion of NO3- plus NO2- between normotensives and hypertensives with normal RVR. Statistically significant associations were seen between diastolic blood pressure and RVR (r = 0.341, P < 0.05) and urinary excretion of NO3- plus NO2- (r = -0.387, P < 0.01) in all hypertensives. These results indicate that there is a subgroup (61%) of hypertensive patients with diminished urine levels of NO3- plus NO2- in which RVR is abnormally increased. Thus, it is suggested that in essential hypertension a diminished renal ability to produce NO by the endothelium may be involved in exaggerated renal vasoconstriction

Decreased excretion of nitrate and nitrite in essential hypertensives with renal vasoconstriction

Most hypertensive patients exhibit increased renal vascular resistance (RVR). This study was designed to investigate whether there exists any relationship between RVR and the production of nitric oxide (NO) in patients with essential hypertension. The study was performed in 49 non-treated patients with mild-to-moderate essential hypertension, and 20 age- and sex-matched normotensive subjects on a controlled sodium diet. Renal hemodynamics was measured in terms of the clearance of para-aminohippuric acid and inulin. Urinary excretion of nitrate and nitrite (NO3- plus NO2-) was determined as an index of NO production. As compared with normotensives, hypertensive patients exhibited higher (P < 0.001) RVR and lower (P < 0.05) urinary excretion of NO3- plus NO2-. With the 100% confidence (upper) limit of the normotensive population as a cut-off point, a subgroup of 30 hypertensives had an abnormally high RVR. The excretion of NO3- plus NO2- was lower (P < 0.005) in hypertensives with high RVR than in normotensives and the remaining hypertensives. No differences were found in the urinary excretion of NO3- plus NO2- between normotensives and hypertensives with normal RVR. Statistically significant associations were seen between diastolic blood pressure and RVR (r = 0.341, P < 0.05) and urinary excretion of NO3- plus NO2- (r = -0.387, P < 0.01) in all hypertensives. These results indicate that there is a subgroup (61%) of hypertensive patients with diminished urine levels of NO3- plus NO2- in which RVR is abnormally increased. Thus, it is suggested that in essential hypertension a diminished renal ability to produce NO by the endothelium may be involved in exaggerated renal vasoconstriction

Subcutaneous anti-COVID-19 hyperimmune immunoglobulin for prevention of disease in asymptomatic individuals with SARS-CoV-2 infection: a double-blind, placebo-controlled, randomised clinical trialResearch in context

Summary: Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols