Novel perspectives regarding the physiologic mechanisms by which gliflozins induce reticulocytosis and erythrocytosis.

Gliflozins provide a breakthrough in the management of type-2 diabetes. In addition to facilitating normoglycemia, these sodium-glucose cotransporter type 2 (SGLT2) inhibitors attenuate obesity, hypertension, dyslipidemia, and fluid retention, reduce cardiovascular morbidity, retard the progression of renal dysfunction, and improve survival. The administration of gliflozins also triggers erythropoietin (EPO) production, with the consequent induction of reticulocytosis and erythrocytosis. The mechanism(s) by which gliflozins induce erythropoiesis is a matter of debate. Whereas the canonical pathway of triggering EPO synthesis is through renal tissue hypoxia, it has been suggested that improved renal oxygenation may facilitate EPO synthesis via noncanonical trails. The latter proposes that recovery of peritubular interstitial fibroblasts producing erythropoietin (EPO) is responsible for enhanced erythropoiesis. According to this hypothesis, enhanced glucose/sodium reuptake by proximal tubules in uncontrolled diabetes generates cortical hypoxia, with injury to these cells. Once transport workload declines with the use of SGLT2i, they recover and regain their capacity to produce EPO. In this short communication, we argue that this hypothesis is incorrect. First, there is no evidence for interstitial cell injury related to hypoxia in the diabetic kidney. Tubular, rather than interstitial cells are prone to hypoxic injury in the diabetic kidney. Moreover, hypoxia, not normoxia, stimulates EPO synthesis by hypoxia-inducible factors (HIFs). Hypoxia regulates EPO synthesis as it blocks HIF prolyl hydroxylases (that initiate HIF alpha degradation), hence stabilizing HIF signals, inducing HIF-dependent genes, including EPO located in the deep cortex, and its production is initiated by the apocrinic formation of HIF-2, colocalized in these same cells.

Glycocalyx Degradation in Ischemia-Reperfusion Injury.

The glycocalyx is a layer coating the luminal surface of vascular endothelial cells. It is vital for endothelial function as it participates in microvascular reactivity, endothelium interaction with blood constituents, and vascular permeability. Structural and functional damage to glycocalyx occurs in various disease states. A prominent clinical situation characterized by glycocalyx derangement is ischemia-reperfusion (I/R) of the whole body as well as during selective I/R to organs such as the kidney, heart, lung, or liver. Degradation of the glycocalyx is now considered a cornerstone in I/R-related endothelial dysfunction, which further impairs local microcirculation with a feed-forward loop of organ damage, due to vasoconstriction, leukocyte adherence, and activation of the immune response. Glycocalyx damage during I/R is evidenced by rising plasma levels of its principal constituents, heparan sulfate and syndecan-1. By contrast, the concentrations of these compounds in the circulation decrease after successful protective interventions in I/R, suggesting their use as surrogate biomarkers of endothelial integrity. In light of the importance of the glycocalyx in preserving endothelial cell integrity and its involvement in pathologic conditions, several promising therapeutic strategies to restore the damaged glycocalyx and to attenuate its deleterious consequences have been suggested. This review focuses on alterations of glycocalyx during I/R injury in general (to vital organs in particular), and on maneuvers aimed at glycocalyx recovery during I/R injury.

Haptoglobin phenotype among patients with IgA nephropathy: Impact on disease progression and response to treatment.

BACKGROUND: IgA nephropathy (IgAN) is characterized by proteinuria, hypertension, and decreased glomerular filtration rate at the time of diagnosis. However, the underlying mechanism is still obscure. The impact of haptoglobin (Hp) phenotype, as a genetic risk factor, on the progression of IgAN has not been studied yet. The current study examines whether Hp phenotype influences IgAN progression and response to treatment. MATERIALS AND METHODS: The study included 40 patients with IgAN, 26 non-IgAN chronic kidney disease (CKD), 114 patients on hemodialysis, and 150 healthy subjects. Blood and urine samples were collected at baseline and 6 months after initiation therapy. Serum creatinine, total proteinuria, and Hp phenotype were determined in all patients and healthy controls. RESULTS: Approximately 17% of IgAN patients were Hp 1-1, 40% Hp 2-1, and 42.5% Hp 2-2. In contrast, in non-IgAN CKD patients, the prevalence of Hp 1-1, Hp 2-1, and Hp 2-2 was 8%, 19%, and 73%, respectively. In hemodialytic patients, prevalence of Hp 1-1, Hp 2-1, and Hp 2-2 was 10.5, 49.1, and 40.4%, respectively. In healthy subjects, the distribution of Hp 1-1, Hp 2-1, and Hp 2-2 was 7, 39, and 54%, respectively. Interestingly, IgAN Hp 2-2 and Hp 2-1 patients were more stable and responded better to treatment with routine therapy than other patients with Hp phenotype. CONCLUSION: The prevalence of Hp 1-1 phenotype is higher in IgAN patients than in the general population in Israel, and even more than in patients with CKD or subjects on hemodialysis. Patients with Hp 2-2 exhibited a better renal response to the routine therapies.

Impact of pretreatment with carnitine and tadalafil on contrast-induced nephropathy in CKD patients.

Objective: The present study assesses whether phosphodiesterase type 5 (PDE-5) inhibitor or carnitine exert nephroprotective effects against clinical contrast-induced nephropathy (CIN).Materials and Methods: The present study consisted of three groups of CKD patients. The first group was control group, who were treated with N-acetyl-L-cysteine 1 day before and on the day of radiocontrast administration. The second one was carnitine group, where the patients were infused with carnitine over 10 min 2 h prior to the radiocontrast administration and 24 h post CT. The third one was PDE-5 inhibitor group, where patients were given tadalafil 2 h prior to the administration of the radiocontrast and in the subsequent day. Urine and blood samples were collected before and at the following time sequence: 2, 6, 12, 24, 48, and 120 h after the contrast administration, for creatinine and NGAL determination.Results: Pretreated with N-acetyl-L-cysteine prior to administration of contrast media (CM) to CKD patients caused a significant increase in urinary but not of plasma neutrophil gelatinase-associated lipocalin (NGAL) and serum creatinine (SCr). In contrast, pretreatment with carnitine prevented the increase in urinary NGAL and reduced SCr below basal levels. Similarly, tadalafil administration diminished the elevation of CM-induced urinary NGAL.Conclusions: These results indicate that carnitine and PDE-5 inhibitors may comprise potential therapeutic maneuvers for CIN.

[PREECLAMPSIA: PATHOGENESIS AND MECHANISMS BASED THERAPEUTIC APPROACHES].

INTRODUCTION: Preeclampsia is a serious complication of pregnancy affecting 3-8% of all pregnancies. It increases the morbidity and mortality of both the fetus and the pregnant woman, especially in developing countries. It deleteriously affects several vital organs, including the kidney, heart, liver, brain, and lung. Although, the pathogenesis of preeclampsia has not yet been fully understood, growing evidence suggests that aberrations in the angiogenic factors levels/activity and coagulopathy are responsible for the clinical manifestations of the disease. The common nominator of tissue damage of all these target organs is endothelial injury, which impedes their normal function. At the renal level, glomerular endothelial injury leads to the development of maternal hypertension and proteinuria. Similarly, this disease can cause hepatic and neurologic dysfunction due to vascular damage. The current review summarizes the recent development in the pathogenesis of this disease state with special focus on novel diagnostic biomarkers and their relevance to potential therapeutic options for preeclampsia. Specifically, we will highlight the renal manifestations of the diseases with emphasis on the involvement of angiogenic factors in vascular injury and how restoration of the angiogenic balance affects the renal and cardiovascular outcome of preeclamptic women.

Effects of carnitine on oxidative stress response to intravenous iron administration to patients with CKD: impact of haptoglobin phenotype.

BACKGROUND: Anemia is a common disorder in CKD patients. It is largely attributed to decreased erythropoietin (EPO) production and iron deficiency. Therefore, besides EPO, therapy includes iron replenishment. However, the latter induces oxidative stress. Haptoglobin (Hp) protein is the main line of defense against the oxidative effects of Hemoglobin/Iron. There are 3 genotypes: 1-1, 2-1 and 2-2. Hp 2-2 protein is inferior to Hp 1-1 as antioxidant. So far, there is no evidence whether haptoglobin phenotype affects iron-induced oxidative stress in CKD patients. Therefore, the present study examines the influence of carnitine treatment on the intravenous iron administration (IVIR)-induced oxidative stress in CKD patients, and whether Hp phenotype affects this response. TRIAL REGISTRATION: Current Controlled Trials ISRCTN5700858. This study included 26 anemic (Hb = 10.23 ± 0.28) CKD patients (stages 3-4) that were given a weekly IVIR (Sodium ferric gluconate, [125 mg/100 ml] for 8 weeks, and during weeks 5-8 also received Carnitine (20 mg/kg, IV) prior to IVIR. Weekly blood samples were drawn before and after each IVIR for Hp phenotype, C-reactive protein (CRP), advanced oxidative protein products (AOPP), neutrophil gelatinase-associated lipocalin (NGAL), besides complete blood count and biochemical analyses. RESULTS: Eight percent of CKD patients were Hp1-1, 19 % Hp2-1, and 73 % Hp2-2. IVIR for 4 weeks did not increase hemoglobin levels, yet worsened the oxidative burden as was evident by elevated plasma levels of AOPP. The highest increase in AOPP was observed in Hp2-2 patients. Simultaneous administration of Carnitine with IVIR abolished the IVIR-induced oxidative stress as evident by preventing the elevations in AOPP and NGAL, preferentially in patients with Hp2-2 phenotype. CONCLUSIONS: This study demonstrates that Hp2-2 is a significant risk factor for IVIR-induced oxidative stress in CKD patients. Our finding, that co-administration of Carnitine with IVIR preferentially attenuates the adverse consequences of IVIR, suggests a role for Carnitine therapy in these patients.

Nephroprotective effects of TVP1022, a non-MAO inhibitor S-isomer of rasagiline, in an experimental model of diabetic renal ischemic injury.

Ischemic acute kidney injury (iAKI) in diabetes mellitus is associated with a rapid deterioration of kidney function, more than in nondiabetic subjects. TVP1022, a non-MAO inhibitor S-isomer of rasagiline, possesses antioxidative and antiapoptotic activities. The current study examines the effects of TVP1022 and tempol on iAKI in diabetic rats. Diabetes was induced by streptozotocin. iAKI was induced by clamping the left renal artery for 30 min in both diabetic and nondiabetic rats. The right intact kidney served as a control. Forty-eight hours following ischemia, urinary flow (V), sodium excretion (UNaV), and glomerular filtration rate (GFR) in both ischemic and nonischemic kidneys were determined. The nephroprotective effects of tempol and TVP1022 were examined in these rats. Hematoxylin and eosin staining, 4-hydroxynonenal (4-HNE) immunofluorescence, and nitrotyrosine immunohistochemistry were performed on renal tissues of the various experimental groups. Compared with normoglycemic rats, iAKI in diabetic animals caused more profound reductions in V, UNaV, and GFR. Tempol and TVP1022 treatment increased GFR two- and four-fold in diabetic ischemic kidney, respectively. Besides hemodynamic perturbations, iAKI markedly increased renal immunoreactive 4-HNE and nitrotyrosine staining in both diabetic and nondiabetic rats. Moreover, iAKI increased medullary necrosis, congestion, and casts. Noteworthy, these increases were to a larger extent in ischemic diabetic kidneys. TVP1022, and to a lesser extent tempol, decreased nitrotyrosine and 4-HNE immunoreactivities and necrosis and cast formation in the renal medulla. TVP1022 treatment improves renal dysfunction and histological changes in an iAKI diabetic model and suggests a role for TVP1022 therapy in kidney injury.

Sacubitril/Valsartan Improves Cardiac Function in Dialysis Patients.

Heart failure (HF) is characterized by the activation of adverse neurohormonal systems and a high mortality rate. Noteworthy, HF is a well-known complication of chronic kidney disease (CKD), especially in end-stage kidney disease (ESKD), where dialysis patients are seven to eight times more likely to encounter cardiac arrest than the general population. Therefore, it is important to develop efficient treatments to improve cardiac function in dialysis patients and eventually reduce the cardiovascular death toll. Sacubitril/valsartan (Sac/Val) is a dual inhibitor/blocker of the neprilysin and angiotensin II receptors, which exert cardioprotective effects among patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved EF (HFpEF). Unfortunately, the drug is not approved for subjects with advanced CKD or dialysis patients due to safety concerns. The current study examined the cardiac effects of Sac/Val in HD patients. Administration of Sac/Val (100-400 mg/day) to 12 hemodialysis (HD) patients with HFrEF for six months gradually improved ejection fraction (EF) independently of morphological changes in cardiac geometry, as assessed by echocardiography (ECHO), and hemodynamic alterations. Interestingly, the Cardiomyopathy Questionnaire (Kansas City KCCQ-12) revealed that quality of life significantly improved after Sac/Val treatment. No major adverse effects were reported in the present study, supporting the safety of Sac/Val at least in these patients and for the applied follow-up period. Collectively, these findings support the use of Sac/Val as a cardioprotective agent in both HD and peritoneal dialysis (PD) patients. Yet, a more comprehensive study is required to establish these findings and to extend the follow-up period for 12 months in order to solidify these encouraging results.

Phosphodiesterase-5 inhibition attenuates early renal ischemia-reperfusion-induced acute kidney injury: assessment by quantitative measurement of urinary NGAL and KIM-1.

Acute kidney injury (AKI) is a common clinical problem that still lacks effective treatment. Phosphodiesterase-5 (PDE5) inhibitors possess anti-apoptotic and anti-oxidant properties, making it a promising therapy for ischemia-reperfusion (I/R) injury of various organs. The present study evaluated the early nephroprotective effects of Tadalafil, a PDE5 inhibitor, in an experimental model of renal I/R. Sprague-Dawley rats were divided into two groups: vehicle-treated I/R (n = 10), and Tadalafil (10 mg/kg po)-treated I/R group (n = 11). After removal of the right kidney and collection of two baseline urine samples, the left renal artery was clamped for 45 min followed by reperfusion for 60, 120, 180, and 240 min. Functional and histological parameters of the kidneys from the various groups were determined. In the vehicle-treated I/R group, glomerular filtration rate was significantly reduced compared with that in normal kidneys. In addition, the ischemic kidney showed remarkable cast formation, necrosis, and congestion, a consistent pattern of acute tubular necrosis. Furthermore, urinary excretion of NGAL and KIM-1, two novel biomarkers of kidney injury, substantially increased following I/R insult. In contrast, Tadalafil treatment resulted in a significant improvement in kidney function and amelioration of the adverse histological alterations of the ischemic kidney. Noteworthy, the urinary excretion of NGAL and KIM-1 markedly decreased in the Tadalafil-treated I/R group. These findings demonstrate that Tadalafil possesses early nephroprotective effects in rat kidneys subjected to I/R insult. This approach may suggest a prophylactic therapy for patients with ischemic AKI.

Corin: a new player in the regulation of salt-water balance and blood pressure.

PURPOSE OF REVIEW: Natriuretic peptides play a key role in regulation of blood pressure and volume homeostasis due to their natriuretic/diuretic and vasodilatory actions. The natriuretic and diuretic responses to natriuretic peptides are markedly attenuated in edematous disease states. Our goal is to review the mechanisms underlying this phenomenon, with special emphasis on the role of corin in salt retention and edema formation in heart failure and nephrotic syndrome, and pathogenesis of hypertension. RECENT FINDINGS: Although three decades have passed since the discovery of atrial natriuretic peptide (ANP), major advances in understanding the physiological and pathophysiological role of the natriuretic peptide family in the regulation of sodium (Na) and water balance are still emerging. As well as ANP, the natriuretic peptide family contains at least two other members: brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). Although encoded by different genes, these natriuretic peptides share a high similarity in their chemical structure and biosynthesis pathway. ANP and BNP are produced from proANP and proBNP, respectively, which are converted into the active forms mainly by corin. The latter is a transmembrane serine protease localized to the heart, and to a lesser extent to the kidneys. Recent studies have demonstrated that perturbations in corin activity lead to elevation of the prohormones at the expense of the mature forms, thereby causing the development of salt-sensitive hypertension, preeclampsia, cardiac hypertrophy, and Na and water retention. SUMMARY: Natriuretic peptides are an important endocrine system in the regulation of body fluid balance and blood pressure. Corin mediates an essential step in the cascade of natriuretic peptide biosynthesis and eventually their action. Thus, it is postulated that aberrations in the normal activity of corin may contribute to cardiovascular and renal diseases.

Pharmacist counseling to cardiac patients in Israel prior to discharge from hospital contribute to increasing patient's medication adherence closing gaps and improving outcomes.

BACKGROUND: Medication non adherence is a global epidemic perplexing phenomenon that is eminent, but not insurmountable. Our first objective was to explore whether providing pharmacist's counseling to cardiac patients prior to discharge can increase patient's medication adherence, and our second objective was to assess whether better medication adherence leads to reduction of hospital readmissions. METHODS: Observational study was conducted among diagnosed cardiac patients using an intervention strategy at discharge from two hospitals in Israel; The Nazareth and the Haemek hospital. 74 patients were recruited between January 2010 and January 2011. Two separate groups were selected; intervention group: 33 patients who prior to discharge received nurse, pharmacist interventions, and control group: 41 patients who had received the nurse and hospital discharge counseling only. RESULTS: Regression analysis for examining the first objective reflected significant effect when having a pharmacist interventions, which explains the increasing 11.6% of the variance in medication adherence, [F change (1,73) = 9.43, p < 0.003]. Stepwise regression analysis for examining the second objective demonstrated that the relation between medication adherence and readmissions was insignificant [F (1,73) = 9.43, n.s]. CONCLUSIONS: While physicians and nurses can have an impact on improving adherence, pharmacists have demonstrated the ability to inform, problem-solve and provide performance support directly to patients.

An Innovative Ultrasound Technique for Early Detection of Kidney Dysfunction: Superb Microvascular Imaging as a Reference Standard.

BACKGROUND: Superb microvascular imaging (SMI) is an innovative ultrasound image processing technique that provides greater detail and better visualization of small branching vessels. We assume that SMI will provide sufficient information regarding the severity of chronic kidney disease (CKD) and reflecting histological changes. AIMS: The aims was to assess the capabilities of SMI imaging regarding the early detection of kidney dysfunction and renal fibrosis in comparison to the reference standard renal biopsy for the early diagnosis of kidney fibrosis. METHODS: SMI was performed in patients (n = 52) with CKD stage 2-5, where some of them underwent biopsy proven CKD and fibrosis as part of the diagnosis. In addition, biochemical tests were performed, including kidney function tests, urine collection for proteinuria, and the estimation of GFR by MDRD or CKD-EPI eGFR in CKD patients and healthy controls (n = 17). All subjects underwent SMI, where vascularity is expressed as the SMI index (a low index reflects low vascularity/fibrosis and vice versa). RESULTS: The SMI vascular index was significantly lower in CKD patients as compared with healthy controls (72.2 ± 12.9 vs. 49.9 ± 16.7%, p < 0.01). Notably, a moderate correlation between the SMI index and eGFR was found among the CKD patients (r = 0.56, p < 0.001). Similarly, a strong correlation was found between SCr and the SMI index of the diseased subjects (r = -0.54, p < 0.001). In patients who underwent renal biopsy, the SMI index corresponded with the histological alterations and CKD staging. CONCLUSIONS: This study demonstrated that SMI imaging may be utilized in CKD patients of various stages for the evaluation of chronic renal morphological changes and for differentiation between CKD grades.

[Neutrophil gelatinase-associated lipocalin (NAGL): a novel biomarker for acute kidney injury].

The incidence of both acute and chronic kidney diseases is persistently increasing and is reaching epidemic proportions. Early therapeutic intervention may significantly decrease the morbidity and mortality rates among these patients. However, the lack of early non-invasive biomarkers has hampered our ability to diagnose kidney diseases as early as possible, and subsequently, to initiate timely, effective, and appropriate treatment. Until recently, no biomarker for kidney disease, except for creatinine was available to clinicians in general and nephrologists in particular. Unfortunately, creatinine is an unreliable indicator during acute and chronic changes in kidney function, since serum creatinine concentrations can vary widely with age, gender, muscle mass, muscle metabolism, medications and hydration status. Secondly, serum creatinine concentrations may not change until a significant amount of kidney function (50-60%) has already been lost. In the last few years various specific biomarkers for kidney diseases were discovered and the most reliable representative is neutrophil gelatinase-associated lipocalin (NGAL), which is the focus of this review. Several studies have demonstrated that plasma and urinary NGAL levels increase two hours after the induction of acute kidney injury (AKI) in several clinical situations such as cardiac surgery, radiocontrast nephropathy, kidney transplantation, hemolytic uremic syndrome and critically ill patients in intensive care unit. Serum and urine concentrations of NGAL increase before those of creatinine, making this biomarker a powerful tool for early detection of renal disease, thus hopefully to reduce the high mortality rate among patients with AKI.

Renal Manifestations of Covid-19: Physiology and Pathophysiology.

Corona virus disease 2019 (COVID-19) imposes a serious public health pandemic affecting the whole world, as it is spreading exponentially. Besides its high infectivity, SARS-CoV-2 causes multiple serious derangements, where the most prominent is severe acute respiratory syndrome as well as multiple organ dysfunction including heart and kidney injury. While the deleterious impact of SARS-CoV-2 on pulmonary and cardiac systems have attracted remarkable attention, the adverse effects of this virus on the renal system is still underestimated. Kidney susceptibility to SARS-CoV-2 infection is determined by the presence of angiotensin-converting enzyme 2 (ACE2) receptor which is used as port of the viral entry into targeted cells, tissue tropism, pathogenicity and subsequent viral replication. The SARS-CoV-2 cellular entry receptor, ACE2, is widely expressed in proximal epithelial cells, vascular endothelial and smooth muscle cells and podocytes, where it supports kidney integrity and function via the enzymatic production of Angiotensin 1-7 (Ang 1-7), which exerts vasodilatory, anti-inflammatory, antifibrotic and diuretic/natriuretic actions via activation of the Mas receptor axis. Loss of this activity constitutes the potential basis for the renal damage that occurs in COVID-19 patients. Indeed, several studies in a small sample of COVID-19 patients revealed relatively high incidence of acute kidney injury (AKI) among them. Although SARS-CoV-1 -induced AKI was attributed to multiorgan failure and cytokine release syndrome, as the virus was not detectable in the renal tissue of infected patients, SARS-CoV-2 antigens were detected in kidney tubules, suggesting that SARS-CoV-2 infects the human kidney directly, and eventually induces AKI characterized with high morbidity and mortality. The mechanisms underlying this phenomenon are largely unknown. However, the fact that ACE2 plays a crucial role against renal injury, the deprivation of the kidney of this advantageous enzyme, along with local viral replication, probably plays a central role. The current review focuses on the critical role of ACE2 in renal physiology, its involvement in the development of kidney injury during SARS-CoV-2 infection, renal manifestations and therapeutic options. The latter includes exogenous administration of Ang (1-7) as an appealing option, given the high incidence of AKI in this ACE2-depleted disorder, and the benefits of ACE2/Ang1-7 including vasodilation, diuresis, natriuresis, attenuation of inflammation, oxidative stress, cell proliferation, apoptosis and coagulation.

Waning Humoral Response 3 to 6 Months after Vaccination with the SARS-COV-2 BNT162b2 mRNA Vaccine in Dialysis Patients.

BACKGROUND AND OBJECTIVES: The short-term reported antibody response to SARS-COV-2 vaccination in dialysis patients is high, with a seroconversion response rate up to 97%. Data on the long-term durability of this response are scarce. Our objective was to characterize the long-term anti-spike antibody level in dialysis patients. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: In an observational study, we measured SARS-COV-2 anti-spike antibody levels in dialysis patients who completed 2 doses of the BNT162b2 mRNA SAR S-COV-2 vaccine at 1, 3 and 6 months after the second vaccine dose. We compared the response to dialysis patients who were infected with COVD-19 and to a control group of healthcare-employees. RESULTS: One hundred and forty-two dialysis patients who had been vaccinated (ages 64 ± 11.9 years, 61% male), 33 dialysis patients who had COVID-19 infection (ages 54 ± 14.3 years, 55% male) and 104 individuals in the control group (ages 50 ± 12.2 years, 44% male) were included. The response rate in the vaccinated dialysis patients was 94%, 78% and 73% at 1, 3 and 6 months after the second vaccine dose. In the COVID-19 infected dialysis group and in the control group, the response rate remained at 100% over 6 months. The percentage of change in antibody levels between one and 6 months was -66% in the vaccinated dialysis group, -28% in the control group (p < 0.001) and +48% in dialysis patients who had been infected with COVID-19 (p < 0.001). A non-responder status at 6 months was associated with a lower albumin level. No serious adverse events following vaccination were reported. In conclusion: the initially high response rate to the BNT162b2 vaccine in dialysis patients decreases rapidly. Our results indicate that an early booster (3rd) dose, at three months after the second dose, may be advised for this population to preserve the humoral immunity.

ACE2, COVID-19 Infection, Inflammation, and Coagulopathy: Missing Pieces in the Puzzle.

Engulfed by the grave consequences of the coronavirus disease 2019 (COVID-19) pandemic, a better understanding of the unique pattern of viral invasion and virulence is of utmost importance. Angiotensin (Ang)-converting enzyme (ACE) 2 is a key component in COVID-19 infection. Expressed on cell membranes in target pulmonary and intestinal host cells, ACE2 serves as an anchor for initial viral homing, binding to COVID-19 spike-protein domains to enable viral entry into cells and subsequent replication. Viral attachment is facilitated by a multiplicity of membranal and circulating proteases that further uncover attachment loci. Inherent or acquired enhancement of membrane ACE2 expression, likely leads to a higher degree of infection and may explain the predisposition to severe disease among males, diabetics, or patients with respiratory or cardiac diseases. Additionally, once attached, viral intracellular translocation and replication leads to depletion of membranal ACE2 through degradation and shedding. ACE2 generates Ang 1-7, which serves a critical role in counterbalancing the vasoconstrictive, pro-inflammatory, and pro-coagulant effects of ACE-induced Ang II. Therefore, Ang 1-7 may decline in tissues infected by COVID-19, leading to unopposed deleterious outcomes of Ang II. This likely leads to microcirculatory derangement with endothelial damage, profound inflammation, and coagulopathy that characterize the more severe clinical manifestations of COVID-19 infection. Our understanding of COVID-ACE2 associations is incomplete, and some conceptual formulations are currently speculative, leading to controversies over issues such as the usage of ACE inhibitors or Ang-receptor blockers (ARBs). This highlights the importance of focusing on ACE2 physiology in the evaluation and management of COVID-19 disease.