Renal safety and survival among acutely ill hospitalized patients treated by blockers of the Renin-Angiotensin axis or loop diuretics: a single-center retrospective analysis.

BACKGROUND: Concern exists regarding the renal safety of blocking the renin-angiotensin system (RAS) during acute illness, especially in the presence of volume depletion and hemodynamic instability. METHODS: We explored the impact of loop diuretics and RAS blockers on the likelihood of developing acute kidney injury (AKI) or acute kidney functional recovery (AKR) among inpatients. Adjusted odds ratio for AKI, AKR and mortality was calculated, using logistic regression models, with subgroup analysis for patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2, corrected for blood pressure measurements. RESULTS: 53,289 patients were included. RAS blockade was associated with reduced adjusted odds ratio for both AKI (0.76, CI 0.70-0.83) AKR (0.55, 0.52-0.58), and mortality within 30 days (0.44, 0.41-0.48), whereas loop diuretics were associated with increased risk of AKI (3.75, 3.42-4.12) and mortality (1.71, 1.58-1.85) and reduced AKR (0.71, 0.66-0.75). Comparable impact of RAS blockers and loop diuretics on renal outcomes and death was found among 6,069 patients with eGFR < 30 ml/min/1.73m2. RAS inhibition and diuretics tended to increase the adjusted odds ratios for AKI and to reduce the likelihood of AKR in hypotensive patients. CONCLUSIONS: Reduced blood pressure, RAS blockers and diuretics affect the odds of developing AKI or AKR among inpatients, suggesting possible disruption in renal functional reserve (RFR). As long as blood pressure is maintained, RAS inhibition seems to be safe and renoprotective in this population, irrespective of kidney function upon admission, and is associated with reduced mortality.

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.

Life-threatening bronchospasm induced by an angiotensin-converting enzyme inhibitor in a chronically ventilated patient: Diagnostic pitfalls and literature review.

Cough- and asthma-like symptoms are common adverse reactions to angiotensin-converting enzyme inhibitors (ACEi). However, attributing these symptoms to the use of ACEi might be masked by clinical confounders. We report a 68-year-old female residing in a long-term acute-care facility for patients requiring prolonged invasive mechanical ventilation treated for years with ACEi. Daily reversible bouts of life-threatening severe bronchospasm gradually developed over 6 weeks and abruptly resolved following the cessation of ACEi treatment. The late appearance of bronchospasm and the unique clinical setup of chronic invasive ventilation in a patient with smoking-related chronic obstructive lung disease are among the principal confounders that delay the identification of the causative association between ACEi and respiratory compromise. Chronic positive pressure ventilation may also conceal small airway reactivity and obstruction, similar to auto-positive end-expiratory pressure (auto-PEEP). Conceivably, angiotensin receptor blockers should be preferred over ACEi in such patients.

Gliflozins, Erythropoietin, and Erythrocytosis: Is It Renal Normoxia- or Hypoxia-Driven?

The introduction of gliflozins in the management of type 2 diabetes mellitus leads to a better control of hyperglycemia, obesity, hypertension, dyslipidemia, and fluid retention. Most importantly, it also improves renal survival and reduces major cardiovascular events and mortality. Gliflozins were also found to induce erythropoietin (EPO) synthesis, leading to reticulocytosis and erythropoiesis. The mechanism(s) by which gliflozins induce erythropoiesis is a matter of debate. Although 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 non-canonical routes. The latter proposes that the recovery of peritubular interstitial fibroblasts producing erythropoietin (EPO) is responsible for enhanced erythropoiesis. According to this hypothesis, enhanced glucose/sodium re-uptake 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 may be wrong and propose that gliflozins likely induce EPO through the documented intensification of renal hypoxia at the corticomedullary junction, related to the translocation of tubular transport from cortical segments to medullary thick ascending limbs. We propose that gliflozins, through intensified hypoxia in this region, trigger local EPO synthesis in peritubular interstitial cells via the canonical pathway of blocking HIF-prolyl hydroxylases (that initiate HIF alpha degradation), with the consequent stabilization of HIF-2 signal and an apocrinic induction of EPO in these same cells.

Reversible 'Unstable' Abdominal Angina Caused by Ruptured Plaque of the Superior Mesenteric Artery: Clinical and Radiological Correlations.

Unstable angina, characteristic of coronary artery disease, is caused by in-situ clot formation complicating ruptured atheromatous plaque. Abdominal angina, however, usually reflects chronic mesenteric ischaemia, caused by multi-vessel stable plaques involving mesenteric arteries. Herein, we describe a patient with new-onset abdominal pain caused by a ruptured atheromatous plaque at the superior mesenteric root. The diagnosis was based on an evident reversible epigastric bruit and high-degree eccentric stenosis caused by a non-calcified atheroma. Symptoms and bruit resolved within 3 weeks on aspirin and statins with regression of the stenotic lesion. Although the condition is likely common, this is the first clear-cut report compatible with 'unstable' abdominal angina, resolved by conservative treatment. LEARNING POINTS: Resembling unstable angina pectoris, ruptured atheromatous plaque in mesenteric vessels can develop, clinically manifested by new-onset abdominal angina.This condition may be reversible under treatment with antiplatelet medications and statins.Searching for abdominal bruit is invaluable in the assessment of unexplained abdominal pain.

Alveolar Hemorrhage Following Positron Emission Tomography/Computed Tomography in 2 Separate Episodes 5 Months Apart.

BACKGROUND Positron emission tomography/computed tomography (PET/CT) has become one of the most prominent modalities worldwide for the diagnosis and surveillance of malignancies. Current clinical imaging guidelines report adverse reactions following PET/CT, especially due to contrast-induced toxicities, such as contrast-induced nephropathy and other rare reactions attributed to a hypersensitivity immune response, such as bronchospasm. Other rare lung toxicities were reported in a few case reports. Herein, we report repeated episodes of alveolar hemorrhage, a novel adverse response to PET/CT, occurring on 2 separate occasions 5 months apart. CASE REPORT A 57 year-old female patient with breast carcinoma managed by mastectomy, adjuvant chemotherapy, irradiation, and hormonal therapy presented with massive alveolar hemorrhage following PET/CT performed for surveillance 13 years after completion of chemotherapy and irradiation. An additional episode of massive alveolar hemorrhage occurred 5 months later following PET/CT, with respiratory failure requiring mechanical ventilation. Fluorine-18 fluorodeoxyglucose ([¹8F] FDG) and iohexol were used for imaging on both occasions. Common causes of alveolar hemorrhage, including malignancy, were excluded. CONCLUSIONS The repeated episodes immediately following PET/CT and the earlier and more intense respiratory failure following the second event raise the possibility of an immune-mediated alveolar hemorrhage in response to either the administration of iodinated radiocontrast agent or to [¹8F] FDG.

A 66-Year-Old Woman with Achondroplasia and Quadriparesis with an Ovarian Cyst Erroneously Diagnosed as Urinary Retention by an Automated Bladder Scan.

BACKGROUND Automated bladder scanning has become a principal tool in the assessment and management of chronically debilitated patients residing in skilled nursing facilities, hospices, and acute inpatient settings. To a large extent, the bladder scan, generally performed by nursing staff, has replaced physical examination while addressing the differential diagnoses of anuria or voiding disturbances that require consideration of urinary catheterization. Health care providers can quickly master this easily performed technique, and currently, due to confidence in the bladder scan finding, physical examination with suprapubic palpation and percussion may be carelessly omitted. The case description presented here illustrates how not performing a physical examination can lead to misdiagnosis caused by misinterpretation of bladder scan findings. CASE REPORT A 66-year-old, quadriparetic, chronically ventilated female patient with achondroplasia underwent repeated hospital referrals and bladder catheterizations for presumed flaccid, neurogenic bladder with urinary retention. This postulated diagnosis was based on occasional reports of urinary catheter obstruction as well as on automated bladder scanning indicating a markedly distended bladder. However, the bladder could not be drained by insertion of urinary catheters. Eventually, a proper physical examination excluded the presence of suprapubic fullness compatible with distended bladder and contradicting bladder scan findings, prompting re-examining an overlooked evaluation of computed tomography that reported a huge ovarian cyst. The patient was found to have intact voiding capabilities and is now weaned from the catheter. CONCLUSIONS This case and the literature review underscore drawbacks in automated bladder scanning. This technique should be used as an adjunctive measure rather than a replacement for a physical examination in the evaluation of voiding disturbances, especially when there are discrepancies between bladder scan findings and the volume of urine drained by catheterization.

Diabetic Proteinuria Revisited: Updated Physiologic Perspectives.

Albuminuria, a hallmark of diabetic nephropathy, reflects not only injury and dysfunction of the filtration apparatus, but is also affected by altered glomerular hemodynamics and hyperfiltration, as well as by the inability of renal tubular cells to fully retrieve filtered albumin. Albuminuria further plays a role in the progression of diabetic nephropathy, and the suppression of glomerular albumin leak is a key factor in its prevention. Although microalbuminuria is a classic manifestation of diabetic nephropathy, often progressing to macroalbuminuria or overt proteinuria over time, it does not always precede renal function loss in diabetes. The various components leading to diabetic albuminuria and their associations are herein reviewed, and the physiologic rationale and efficacy of therapeutic interventions that reduce glomerular hyperfiltration and proteinuria are discussed. With these perspectives, we propose that these measures should be initiated early, before microalbuminuria develops, as substantial renal injury may already be present in the absence of proteinuria. We further advocate that the inhibition of the renin-angiotensin axis or of sodium-glucose co-transport likely permits the administration of a normal recommended or even high-protein diet, highly desirable for sarcopenic diabetic patients.

Do Perceptions about Palliative Care Affect Emergency Decisions of Health Personnel for Patients with Advanced Dementia?

Decision analysis regarding emergency medical treatment in patients with advanced dementia has seldom been investigated. We aimed to examine the preferred medical treatment in emergency situations for patients with advanced dementia and its association with perceptions of palliative care. We conducted a survey of 159 physicians and 156 nurses from medical and surgical wards in two tertiary hospitals. The questionnaire included two case scenarios of patients with advanced dementia presenting gastrointestinal bleeding (scenario I) or pneumonia (scenario II) with a list of possible interventions and 11 items probing perceptions towards palliative care. Low burden interventions such as laboratory tests and intravenous administration of antibiotics/blood were preferred. Palliative measures such as analgesia/sedation were chosen by about half of the participants and invasive intervention by 41.6% (gastroscopy in scenario I) and 37.1% (intubation/mechanical ventilation in scenario II). Medical ward staff had a more palliative approach than surgical ward staff in scenario I, and senior staff had a more palliative approach than junior staff in scenario II. Most participants (90.4%) agreed that palliative care was appropriate for patients with advanced dementia. Stress in caring for patients with advanced dementia was reported by 24.5% of participants; 33.1% admitted fear of lawsuit, 33.8% were concerned about senior-level responses, and 69.7% were apprehensive of family members' reaction to palliative care. Perceptions of health care workers towards palliative care were associated with preferred treatment choice for patients with advanced dementia, mainly in scenario II. Attitudes and apprehensions regarding palliative care in these situations may explain the gap between positive attitudes towards palliative care and the chosen treatment approach. Acquainting emergency care practitioners with the benefits of palliative care may impact their decisions when treating this population.

Changing serum creatinine in the detection of acute renal failure and recovery following radiocontrast studies among acutely ill inpatients: Reviewing insights regarding renal functional reserve gained by large-data analysis.

A rise in serum creatinine (SCr) is widely used for the detection and definition of evolving acute kidney injury (AKI). Yet, it takes time for SCr to re-adjust in response to changes in glomerular filtration rate (GFR), and subtle transient changes in GFR may remain concealed. Additionally, it cannot differentiate altered glomerular hemodynamics and pre-renal failure from true renal tissue injury, necessitating additional clinical and laboratory diagnostic tools. While these features limit the usefulness of SCr and subsequently estimated GFR (eGFR) at a single time point for the individual patient, their overall pattern of changes along time in a large cohort of hospitalized patients may provide a powerful perspective regarding the detection and assessment of shifting kidney function in this population. Herein we review our experience running large data analyses, evaluating patterns of day-to-day changes in SCr among inpatients, occurring around the exposure to iodinated radiocontrast agents. These large data evaluations helped substantiating the existence of contrast-induced nephropathy in patients with advanced renal failure, underscoring the impact of predisposing and confounding factors. It also provides novel insights regarding a phenomenon of "acute kidney functional recovery" (AKR), and illustrate that the incidence of AKI and AKR along the scale of baseline kidney function co-associates and is inversely proportional to kidney function. This can be attributed to renal functional reserve, which serves as a buffer for up-and-down changes in GFR, forming the physiologic explanation for concealed subclinical AKI.

Severe Protracted Hypophosphatemia in a Patient with Persistent Vegetative State on Long-Term Assisted Respiratory Support.

BACKGROUND Phosphorous is an essential component of cell structure and physiology, and is required for energy conservation and expenditure. Severe hypophosphatemia can lead to profound dysfunction and injury affecting most organs and can be life-threatening. It can also compromise weaning of mechanically ventilated patients. Long-term assisted ventilatory care in ambulatory or inpatient settings is an expanding medical service for patients with various forms of persistent or progressive incapacitating diseases. Hypophosphatemia, caused by respiratory alkalosis, has been reported in critical-care settings, but its occurrence in medically stable patients requiring long-term respiratory support has not been thoroughly investigated. CASE REPORT We report the case of a ventilated patient in a chronic vegetative state displaying progressive hypophosphatemia spanning over 3 months, with plasma levels gradually declining to 0.8 mg/dL. Evaluation did not reveal conditions leading to diminished phosphate absorption or enhanced urinary phosphate excretion, but it identified respiratory alkalosis related to a recent increase in target minute-volume ventilation in the adaptive support ventilation (ASV) mode as the cause of hypophosphatemia. Despite the very low plasma phosphate level, the patient was asymptomatic, probably because this type of hypophosphatemia may not represent physiologically significant intracellular phosphate depletion. The respiratory alkalosis resolved upon decreasing the target minute-volume ventilation settings, and serum phosphate was normalized. CONCLUSIONS Since blood gases are not routinely monitored in respiratory and hemodynamically stable patients on long-term respiratory support, hypophosphatemia may herald the development of significant respiratory alkalosis. Assessment of acid-base balance is thus warranted in patients receiving long-term ventilation, especially in those developing hypophosphatemia.

Divergent impacts of tocilizumab and colchicine in COVID-19-associated coagulopathy: the role of alpha-defensins.

Patients who are severely affected by coronavirus disease 2019 (COVID-19) may develop a delayed onset 'cytokine storm', which includes an increase in interleukin-6 (IL-6). This may be followed by a pro-thrombotic state and increased D-dimers. It was anticipated that tocilizumab (TCZ), an anti-IL-6 receptor monoclonal antibody, would mitigate inflammation and coagulation in patients with COVID-19. However, clinical trials with TCZ have recorded an increase in D-dimer levels. In contrast to TCZ, colchicine reduced D-dimer levels in patients with COVID-19. To understand how the two anti-inflammatory agents have diverse effects on D-dimer levels, we present data from two clinical trials that we performed. In the first trial, TCZ was administered (8 mg/kg) to patients who had a positive polymerase chain reaction test for COVID-19. In the second trial, colchicine was given (0·5 mg twice a day). We found that TCZ significantly increased IL-6, α-Defensin (α-Def), a pro-thrombotic peptide, and D-dimers. In contrast, treatment with colchicine reduced α-Def and Di-dimer levels. In vitro studies show that IL-6 stimulated the release of α-Def from human neutrophils but in contrast to colchicine, TCZ did not inhibit the stimulatory effect of IL-6; raising the possibility that the increase in IL-6 in patients with COVID-19 treated with TCZ triggers the release of α-Def, which promotes pro-thrombotic events reflected in an increase in D-dimer levels.

Renal functional recovery among inpatients: A plausible marker of reduced renal functional reserve.

Renal functional reserve (RFR) reflects the ability of the kidney to enhance glomerular filtration rate (GFR) in response to a protein load. Chronic kidney disease (CKD) leads to diminished RFR, since the capacity for whole-body GFR to increase through hyperfiltration of remaining nephrons is limited. Evaluating 41,456 inpatients following computerised tomography we reported many exhibiting acute kidney injury (AKI) but more patients with recovering kidney function (AKR), presumably reflecting resolution of their critical conditions. The incidences of AKI and AKR were closely co-associated and were both inversely correlated with baseline kidney function. We discuss this phenomenon, arguing that AKR among inpatients with an acute illness, like AKI, may often reflect underlying subtle CKD with diminished RFR.

[RADIOCONTRAST NEPHROPATHY: MYTHS OR REALITY? THE VALUE OF PROPENSITY MATCHING APPLIED FOR LARGE DATA RETROSPECTIVE ANALYSES].

INTRODUCTION: Reviewed are three studies we conducted, assessing the risk of contrast nephropathy in hospitalized patients undergoing computerized tomography. These were retrospective large data analyses at a single tertiary care facility, using meticulous and compound propensity score matching and inverse probability of treatment weighting. These studies indicate that overall, the risk of contrast nephropathy is likely negligible, with the exception of patients with grades 4-5 renal failure at baseline (eGFR<30 ml/min/1.73m2), with an odds ratio of 1.51 to develop AKI, associated with increased mortality as compared with patients undergoing non-enhanced imaging. We also assessed the incidence and magnitude of improved kidney function (acute kidney recovery) around imaging, underscoring its potential to mask subclinical AKI. These studies illustrate the strengths of large data analysis with advanced statistical tools.