Hyperferritinemia in patients with COVID-19: An opportunity for iron chelation?

Studies from China on COVID-19 revealed that nonsurvivors had cytokine storm with high IL-6 and hyperferritinemia. Iron liberated from necrotic cells may catalyze free radical production and amplify lipid peroxidation causing membrane dysfunction and multiorgan failure. Consequently, iron chelators have been successfully utilized in various experimental and clinical models of cytokine storm and multiorgan damage, such as in ischemia-reperfusion injury, sepsis, and infections. Since viral replication may be influenced by iron accumulation, iron chelation has been proven beneficial in a variety of viral infections, such as HIV-1, hepatitis B virus, Mengovirus, Marburg hemorrhagic fever, Enterovirus 71, and West Nile virus. In this commentary, we elaborate on the idea of considering iron chelation as a therapeutic modality in patients with severe COVID-19 infection. For critically ill patients in the ICU, intravenous deferoxamine would provide sufficient and rapid iron chelation to ameliorate cytokine storm, whereas in less severe cases an oral chelator could prevent the development of excessive inflammatory response.

Competing Effects of Renin Angiotensin System Blockade and Sodium-Glucose Cotransporter-2 Inhibitors on Erythropoietin Secretion in Diabetes.

BACKGROUND: Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values. SUMMARY: The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2-3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.

Assessment of serum bioactive hepcidin-25, soluble transferrin receptor and their ratio in predialysis patients: Correlation with the response to intravenous ferric carboxymaltose.

BACKGROUND: No reliable biomarker exists to predict responsiveness to intravenous (IV) iron (Fe) in iron deficient patients with CKD. We aimed to investigate the clinical value of bioactive Hepcidin-25 and soluble Transferrin Receptor (sTfR) levels in predialysis patients. PATIENTS AND METHODS: In this prospective study 78 stable stage III-IV CKD predialysis patients with (responders) (40 patients) and without (non-responders) (38 patients) adequate erythropoiesis after IV administration of ferric-carboxymaltose (FCM). Patients were divided in two groups according to their response to IV administration of ferric-carboxymaltose (FCM). Along with measurements of common hematologic and blood chemistry parameters, determinations of sTfR and bioactive Hepcidin-25 were performed. RESULTS: Hepcidin-25 levels were lower in the responders (p=0.025), while sTfR and sTfR/Hepcidin-25 ratio were higher (p<0.01 and p=0.002 respectively). Diagnostic efficacy indicated cut off point of 1.49 for Hepcidin-25 had sensitivity 84% and specificity 48%, while cut off point of 1.21 for sTfR/Hepcidin-25 ratio had sensitivity 82% and specificity 52% to predict correctly response to iron supplementation therapy. Furthermore, log sTfR/Hepcidin-25 correlated negatively with hs-CRP (p=0.005) and IL-6 (p<0.04) in non-responders, while such correlations were not found in responders (p>0.05). CONCLUSIONS: These results suggest that lower Hepcidin-25, as well as higher sTfR and sTfR/Hepcidin-25 ratio were significant predictors of favorable hemoglobin response within a month after IV administration of FCM in patients with CKD. Further experiments and clinical studies in other groups of patients are needed to better elucidate the role of Hepcidin-25 and sTfR/Hepcidin-25 ratio as predictors of response to intravenous iron administration.

Circulating resistin is a significant predictor of mortality independently from cardiovascular comorbidities in elderly, non-diabetic subjects with chronic kidney disease.

CONTEXT: Resistin is associated with inflammation, atherosclerosis and cardiovascular (CV) disease. OBJECTIVE: To associate circulating resistin with all-cause and CV mortality in chronic kidney disease (CKD) patients. METHODS: Serum resistin was determined in a cohort of 80 elderly, non-diabetic patients with stable CKD at different stages in a follow-up period of 5 years. RESULTS: Circulating resistin was significantly elevated in deceased compared to alive patients. Resistin emerged as an independent biomarker of all-cause and CV mortality after a 5-year follow-up period. CONCLUSION: Elevated circulating resistin was a significant independent predictor of CV and all-cause mortality in elderly, non-diabetic CKD patients.

Correlates of serum resistin in elderly, non-diabetic patients with chronic kidney disease.

BACKGROUND: Renal function may be a major determinant of resistin levels, since most studies revealed association between elevated resistin levels and decreased glomerular filtration rate (GFR) in patients with chronic kidney disease (CKD). The aim of the present study was to test the hypothesis whether serum resistin is associated with markers of malnutrition and inflammation in elderly non-diabetic adults in different stages of CKD including hemodialysis. METHODS: This was a cross-sectional study of 80 elderly patients divided in four groups of 20 patients each according to eGFR and matched for age (+/- 5 years) and gender. Patients with eGFR more than 1.5 mL/second served as controls. Multivariate regression was used to evaluate the association of resistin with eGFR, demographic, metabolic and inflammatory markers, and insulin resistance. Hematological, biochemical, and immunochemical analyses were performed using commercially available enzyme immunoassays. RESULTS: Our results showed that: 1) serum resistin levels were two times higher in patients with advanced CKD especially those undergoing hemodialysis compared to controls, 2) in univariate analysis, resistin levels correlated directly with Tumor Necrosis Factor-alpha (TNF-alpha), high sensitive C-Reactive Protein (hsCRP), and serum phosphate and inversely correlated with albumin, eGFR, and hematocrit levels. We failed to reveal any relationship between resistin levels and Homeostasis Model Assessment Score of Insulin Resistance (HOMA-IR), body mass index (BMI), cholesterol and leptin levels, 3) in multivariate analysis, only TNF-alpha (p < 0.001) and hsCRP (p = 0.032) were the most important independent determinants of serum resistin levels. CONCLUSIONS: These results indicate that resistin increases as GFR declines and may be involved in the malnutrition-inflammation state and the reverse epidemiology phenomenon present in elderly, non-diabetic patients with CKD.

Hemodialysis-induced alterations in macular thickness measured by optical coherence tomography in diabetic patients with end-stage renal disease.

BACKGROUND/AIMS: To evaluate changes in macular thickness measured by optical coherence tomography (OCT) during a hemodialysis (HD) session in diabetic patients with end-stage renal disease. METHODS: 72 eyes of 36 diabetic patients with and without macular edema were evaluated before and immediately after an HD session. Average and maximum macular thicknesses in the central disk (6 mm in diameter) and total macular volume were measured. RESULTS: In the eyes with diabetic macular edema, maximum macular thickness within the central disk of 6 mm, and mainly in its peripheral parts, was significantly reduced by 31.18 ± 4.18 µm after HD (p < 0.001). Average macular thickness and total macular volume were also significantly reduced (p = 0.003 and 0.015, respectively). In diabetic eyes without edema, maximum macular thickness decreased significantly by 11.21 ± 1.98 µm after HD (p < 0.001), while average macular thickness and total macular volume decreased slightly (p = 0.034, p = 0.043). Best-corrected visual acuity failed to change. We found a significant association of macular thickness changes with osmolality reduction and the presence of macular edema. CONCLUSION: HD decreases macular thickness in diabetic patients with macular edema, while there exists a less-pronounced effect in diabetic eyes without edema.

Case Report of Cardiorenal Syndrome with Ascites and Listeria monocytogenes Peritonitis: The Role of Large-Volume Paracentesis and Albumin Replacement.

BACKGROUND Spontaneous bacterial peritonitis is a common infection in hospitalized patients with ascites, particularly in patients with cirrhosis. Spontaneous bacterial peritonitis is often associated with acute kidney injury. The causative agents of spontaneous bacterial peritonitis are usually gram-negative bacteria, but lately, the prevalence of spontaneous bacterial peritonitis caused by gram-positive bacteria is rising. CASE REPORT In this report, we present the case of a 77-year-old woman with a history of cardiorenal syndrome with ascites and chronic kidney disease who was admitted with diarrhea, fever, and abdominal pain. Ascitic fluid paracentesis revealed spontaneous bacterial peritonitis due to Listeria monocytogenes. During hospitalization, her ascites gradually enlarged and her kidney function deteriorated. The deterioration of kidney function was at least partially attributed to sepsis caused by spontaneous bacterial peritonitis. In addition to proper antibiotic therapy with ampicillin and daily hemodialysis sessions, large-volume paracentesis and albumin infusions were instituted. After 5 days, she showed a fast improvement, the ascites subsided, and her renal function returned to baseline. CONCLUSIONS Spontaneous bacterial peritonitis caused by Listeria monocytogenes is associated with a poor outcome. Acute kidney injury in patients with spontaneous bacterial peritonitis is common and related with a poor outcome. Data about the role of large-volume paracentesis and albumin replacement in patients with spontaneous bacterial peritonitis are still ambiguous. In the literature, all patients with spontaneous bacterial peritonitis due to Listeria monocytogenes who underwent large-volume paracentesis survived.

Discontinuation of the renin-angiotensin system inhibitors improves erythropoiesis in patients with lower-risk myelodysplastic syndromes.

Renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme inhibitors (ACEis) or angiotensin-receptor blockers (ARBs) has been related to anemia in various situations. We aimed to investigate whether discontinuation of RAS inhibitors improves erythropoiesis in patients with lower-risk myelodysplastic syndromes (LR-MDSs). Seventy-four patients with LR-MDS were divided into three groups matched for gender and age. Group A consisted of 20 hypertensive patients who discontinued RAS inhibitors and received alternative medications. Group B consisted of 26 patients who continued to receive ACEi/ARB and Group C included 28 patients (50% hypertensive) never exposed to ACEi/ARB. Half of the patients in each group were under treatment with recombinant human erythropoietin (rHuEPO). Data were collected at baseline and after 3, 6 and 12 months. Group A showed a significant increase in hemoglobin from 10.4 ± 1g/dL at baseline to 12.6 ± 1.2 g/dL after 12 months (p = 0.035) and in hematocrit (31.4 ± 3% versus 37.9 ± 4%, p = 0.002). Incident anemia decreased from 100% at baseline to 60% at 12 months (p = 0.043) despite a concomitant dose reduction in rHuEPO by 18% (p = 0.035). No changes in hemoglobin and hematocrit were observed in both Group B and Group C. In the subset of patients not treated with rHuEPO, improvement of erythropoiesis was found only in Group A, as measured by changes in hemoglobin (11.5 ± 1 g/dL versus 12.4 ± 1.3 g/dL, p = 0.041) and hematocrit (34.5 ± 3% versus 37.1 ± 4%, p = 0.038) after 12 months. In contrast, Group B and Group C decreased hemoglobin and hematocrit after 12 months (p < 0.05). In conclusion, discontinuation of ACEi/ARB in LR-MDS patients is followed by a significant recovery of erythropoiesis after 12 months.

The role of the renin-angiotensin system in the regulation of erythropoiesis.

The renin-angiotensin system is the major regulator of blood pressure by virtue of controlling vascular resistance and plasma volume. Much less recognition exists for the role of the renin-angiotensin system in regulating erythropoiesis, a biological function critical for oxygen delivery to tissues. In this review, we present evidence that angiotensin II (Ang II) is a physiologically important regulator of erythropoiesis with 2 key actions. First, Ang II is a growth factor of erythroid progenitors and, in cooperation with erythropoietin, increases red blood cell mass. Second, Ang II acts as an erythropoietin secretagogue to maintain increased erythropoietin levels despite increments in hematocrit. Among a multitude of physiologic and pathophysiologic implications, these lines of evidence provide an explanation for the effect of angiotensin-converting enzyme inhibitors and Ang II type 1 receptor blockers to decrease hematocrit or cause anemia in various clinical conditions.

Effects of interleukin-6 on depression risk in dialysis patients.

BACKGROUND/AIMS: Depression represents the most frequent psychiatric disorder in nephrology. Cytokines, and especially IL-6, were found to be elevated in depressed patients with normal renal function. The objective of this pilot study was to examine the relationship between depression and cytokines (IL-6, TNF-alpha, and IL-10) in patients with end-stage kidney disease (ESKD). METHODS: We studied 44 stable patients with ESKD for 71 +/- 66 months (32 males; 64 +/- 13 years; 27 on hemodialysis and 17 on peritoneal dialysis). The control group included 20 healthy age- and gender-matched individuals (12 males; 60 +/- 12 years). Depression was assessed by the Zung Self-Rating Depression Scale (ZS). Nephelometry for high-sensitivity CRP and ELISA kits for IL-6, IL-10 and TNF-alpha were used. RESULTS: Compared to controls, patients with ESKD had higher ZS scores (56.8 +/- 16.8 vs. 44 +/- 12.7, p < 0.01), WBC (7,987 +/- 2,347 vs. 6,413 +/- 870/mm(3), p < 0.01), ESR (36.3 +/- 15.8 vs. 9.4 +/- 3.3 mm, p < 0.001), TNF-alpha (52 +/- 18.4 vs. 10.7 +/- 2.8 pg/ml, p < 0.001) and IL-6 (6.3 +/- 4 vs. 1.8 +/- 0.4 pg/ml, p < 0.001). No differences in high-sensitivity CRP and IL-10 were noted between the ESKD and control groups. Serum IL-6 levels were the only parameter positively correlated with the values of the ZS score in ESKD patients (r = 0.34, p < 0.02). CONCLUSIONS: IL-6 may play a role in the pathogenesis of depression in patients with ESKD.

Inhibition of the renin-angiotensin system in the cardiorenal syndrome with anaemia: a double-edged sword.

: The term 'cardiorenal syndrome' (CRS) was introduced to describe problems related to the simultaneous existence of heart and renal insufficiency. The prevalence of anaemia in CRS is high and increases the risk of hospitalizations and death. Renin-angiotensin system (RAS) inhibition is the cornerstone therapy in cardiovascular and renal medicine. As angiotensin II regulates both glomerular filtration rate (GFR) and erythropoiesis, RAS inhibition can further deteriorate renal function and lower hematocrit or cause anaemia in patients with heart failure. The aim of this review is to explore the relationship among CRS, anemia and administration of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) and summarize the evidence suggesting that RAS inhibition may be considered an iatrogenic cause of deterioration of CRS with anemia. It should be emphasized however, that RAS inhibition reduces mortality in both groups with and without worsening of renal function, and therefore, no patient with CRS should be denied an ACEi or ARB trial without careful evaluation.

Chloride Intracellular Channel 4 Overexpression in the Proximal Tubules of Kidneys from the Spontaneously Hypertensive Rat: Insight from Proteomic Analysis.

BACKGROUND: Hypertensive nephropathy, a leading cause of declining kidney function, is a multifactorial process not well understood. In order to elucidate biological processes and identify novel macromolecular components crucially involved in the process of kidney damage, the application of system biology approaches, like proteomics, is required. METHODS: Proteomic studies were performed using the renal parenchyma of spontaneously hypertensive rats (SHR) and their normotensive Wistar Kyoto controls. Animals were sacrificed at early time intervals (6, 13, and 20 weeks after birth), the renal tissue extract was subjected to two-dimensional gel electrophoresis, differential expressed proteins were identified, and altered pathways were evaluated. One specific protein, chloride intracellular channel 4 (CLIC4), not implicated so far in the development of hypertension and nephrosclerosis, was further studied by Western blotting, immunohistochemistry and immunofluorescence. RESULTS: Proteomic analysis identified several pathways/processes and organelles (mitochondria) as being affected from the early stages of hypertension. CLIC4 was overexpressed in SHR at all 3 time intervals examined. This finding was confirmed by Western blotting and by immunohistochemistry and immunofluorescence; these morphological techniques demonstrated that CLIC4 was almost exclusively localized at the apical surface of the proximal tubular epithelial cells. CONCLUSIONS: Our studies provide evidence that major changes occur in the renal parenchyma from early stages of the development of hypertension. The overexpression of CLIC4 suggests that alterations in the proximal tubular compartment during hypertension should be further examined and that CLIC4 may be a useful early marker of renal tubular alterations due to elevated blood pressure.

Transdermal Delivery of AT1 Receptor Antagonists Reduce Blood Pressure and Reveal a Vasodilatory Effect on Kidney Blood Vessels.

BACKGROUND: The Renin Angiotensin System (RAS) is pharmacologically targeted to reduce blood pressure, and patient compliance to oral medications is a clinical issue. The mechanisms of action of angiotensin receptor blockers (ARBs) in reducing blood pressure are not well understood and are purported to be via a reduction of angiotensin II signaling. OBJECTIVE: We aimed to develop a transdermal delivery method for ARBs (losartan potassium and valsartan) and to determine if ARBs reveal a vasodilatory effect of the novel RAS peptide, alamandine. In addition, we determined the anti-hypertensive effects of the transdermal delivery patch. METHODS: In vitro and in vivo experiments were performed to develop an appropriate therapeutic system, promising an alternative and more effective therapy in the treatment of hypertension. A variety of penetration enhancers were selected such as isopropyl myristate, propylene glycol, transcutol and dimenthyl sulfoxide to obtain a constant release of drugs through human skin. Small resistance vessels (kidney interlobar arteries) were mounted in organ baths and incubated with an ARB. Vasodilatory curves to alamandine were constructed. RESULTS: The in vivo studies demonstrate that systemic absorption of valsartan and losartan potassium using the appropriate formulations provide a steady state release and anti-hypertensive effect even after 24 hours of transdermal administration. No apparent skin irritations (erythema, edema) were observed with the tested formulations. We also show that blocking the AT1 receptor of rabbit interlobar arteries in vitro reveals a vasodilatory effect of alamandine. CONCLUSION: This study reveals the potential mechanism of AT1 receptor blockade via alamandine, and is an important contribution in developing a favorable, convenient and painless antihypertensive therapy of prolonged duration through transdermal delivery of AT1 blockers.

IgA nephropathy in Greece: data from the registry of the Hellenic Society of Nephrology.

BACKGROUND: Natural history, predisposing factors to an unfavourable outcome and the effect of various therapeutic regimens were evaluated in a cohort of 457 patients with immunoglobulin A nephropathy (IgAN) and follow-up of at least 12 months. METHODS: Patients with normal renal function and proteinuria <1 g/24 h as well as those with serum creatinine (SCr) >2.5 mg/dL and/or severe glomerulosclerosis received no treatment. Patients with normal or impaired renal function and proteinuria >1 g/24 h for >6 months received daily oral prednisolone or a 3-day course of intravenous (IV) methylprednisolone followed by oral prednisolone per os every other day or a combination of prednisolone and azathioprine. The clinical outcome was estimated using the primary endpoints of end-stage renal disease and/or doubling of baseline SCr. RESULTS: The overall 10-year renal survival was 90.8%, while end-stage renal disease and doubling of baseline SCr developed in 9.2% and 14.7% of patients, respectively. Risk factors related to the primary endpoints were elevated baseline SCr, arterial hypertension, persistent proteinuria >0.5 g/24 h and severity of tubulointerstial fibrosis. There was no difference in the clinical outcome of patients treated by the two regimens of corticosteroids; nevertheless, remission of proteinuria was more frequent in patients who received IV methylprednisolone (P = 0.000). The combination of prednisolone with azathioprine was not superior to IV methylprednisolone followed by oral prednisolone. Side effects related to immunossuppressive drugs were observed in 12.8% of patients. CONCLUSION: The clinical outcome of patients with IgAN was related to the severity of clinical and histological involvement. The addition of azathioprine to a corticosteroid-based regimen for IgAN does not improve renal outcome.

Chronic acid-base perturbations in hemodialysis patients treated with sevelamer hydrochloride: a two-year follow-up study.

Sevelamer hydrochloride (HCl) contains multiple amines that may cause a significant dietary acid load. To evaluate the impact of sevelamer on arterial blood gases, we followed two groups of stable hemodialysis patients for 24 months. The Sevelamer Group (n = 7) did not achieve the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) goals for phosporus and Ca x P product and was switched from a calcium-based to sevelamer-based regimen. The Calcium Group (n = 7) achieved those goals and remained on calcium salts. Following sevelamer administration, a deterioration of chronic metabolic acidosis was revealed, which lasted throughout the study. Sevelamer therapy was associated with reduced cholesterol levels, improved serum phosphate, and Ca x P product, which facilitated the management of secondary hyperparathyroidism. No significant changes in acid-base status or other parameter tested were found in the Control Group. In conclusion, sevelamer intake caused small but persistent acid-base disturbances, which did not neutralize sevelamer's beneficial effects on mineral and lipid metabolism.

Hematologic and renal improvement of monoclonal immunoglobulin deposition disease after treatment with bortezomib-based regimens.

Monoclonal immunoglobulin deposition disease (MIDD) is characterized by non-organized immunoglobulin-fragments along renal basement membranes with subsequent organ deterioration. Treatment is directed against the immunoglobulin-producing clone. We treated 18 MIDD patients with bortezomib-based regimens (12 received bortezomib-dexamethasone, 6 bortezomib-dexamethasone with cyclophosphamide). Eleven (61%) patients achieved a hematologic response, but only 6 (33.3%) reached to a complete (CR) or very good partial response (VGPR). Regarding renal outcomes 77.8 and 55.6% had ≥30 and ≥50% reduction of proteinuria, respectively, but 33.3% ended up in end-stage renal disease (ESRD). Among patients with CR or VGPR, median eGFR improvement was 7.7 ml/min/1.73 m2 and none progressed to ESRD, but no significant renal recovery was observed in patients achieving a partial response or less, with 50% progressing to dialysis. Pretreatment eGFR seems to influence renal prognosis. Bortezomib-based treatment is considered an effective approach in MIDD and reaching to a deep hematologic response (≥VGPR) conditionally controls further renal declining.

Angiotensin II fails to induce preconditioning in vivo--the protective role of myocardial stretch due to pressure overload.

BACKGROUND: Angiotensin II (Ang) has been successfully used as a preconditioning analogue in isolated rabbit hearts. It is also known that local concentrations of Ang accelerate ischemic injury in vivo, while activation of stretch receptors protects ischemic hearts. OBJECTIVES: First, to investigate further whether Ang can mimic preconditioning in vivo. Second, to test the hypothesis that there is an activation of stretch receptors, and that the larger infarct from the left atrium Ang compared with that from the intravenous Ang may be associated with the ischemic injury caused by local administration. METHODS: Male rabbits were divided into four groups - a control group, an ischemic preconditioning group with 5 min ischemia, a left atrial group and an intravenous group with 5 min Ang infusion. All animals were subjected to prolonged ischemia and reperfusion. A second series of experiments was also performed with five groups that had a 5 min mechanical obstruction of the aorta (Ao clamp), also used as a preconditioning analogue with or without the stretch receptor blocker gadolinium (Gd). RESULTS: Contrary to what was expected from the ex vivo experiments, Ang failed to mimic preconditioning (infarct size 39.6 6.1%, 13.7 4.1%, 52.2% 6.9% and 31.2 4.8%, respectively for the above groups). Interestingly, however, when Ang was infused intravenously, it produced a significantly smaller infarct compared with that observed after the same dose was infused into the left atrium (P<0.05). The infarct size was 17.0 3.7% in the Ao clamp group, which was an effect completely prevented by Gd (45.8 4.2%, P<0.01). Although Gd did not alter infarct size in the control and ischemic preconditioning groups, it increased infarct size when added to the intravenous Ang group (Gd-intravenous Ang 48.6 3.3%, P<0.05 compared with intravenous Ang). CONCLUSIONS: Ang fails to mimic preconditioning in vivo, but salvage of ischemic myocardium can be emanated from pressure overload.

Impact of hemodialysis on dyspnea and lung function in end stage kidney disease patients.

BACKGROUND: Respiratory symptoms are usually underestimated in patients with chronic kidney disease undergoing maintenance hemodialysis. Therefore, we set out to investigate the prevalence of patients chronic dyspnea and the relationship of the symptom to lung function indices. METHODS: Twenty-five clinically stable hemodialysis patients were included. The mMRC dyspnea scale was applied before and after hemodialysis. Spirometry, single breath nitrogen test, arterial blood gases, static maximum inspiratory (P(imax)) and expiratory (P(emax)) muscle pressures, and mouth occlusion pressure (P 0.1) were also measured. RESULTS: Despite normal spirometry, all patients (100%) reported mild to moderate degree of chronic dyspnea pre which was reduced after hemodialysis. The sole predictor of (Δ) mMRC was the (Δ) P 0.1 (r = 0.71, P < 0.001). The P(imax) was reduced before and correlated with the duration of hemodialysis (r = 0.614, P < 0.001), whilst after the session it was significantly increased (P < 0.001). Finally (Δ) weight was correlated with the (Δ) P(imax) %pred (r = 0.533, P = 0,006) and with the (Δ) CV (%pred) (r = 0.65, P < 0.001). CONCLUSION: We conclude that dyspnea is the major symptom among the CKD patients that improves after hemodialysis. The neuromechanical dissociation observed probably is one of the major pathophysiologic mechanisms of dyspnea.

Spironolactone improves endothelial and cardiac autonomic function in non heart failure hemodialysis patients.

OBJECTIVES: Hemodialysis patients have a cardiovascular mortality rate of 20-40 times that of the general population. Aldosterone inhibition by spironolactone has exerted beneficial, prognostically significant cardiovascular effects in patients with heart failure maintained on hemodialysis or peritoneal dialysis. Our aim was to investigate spironolactone's effect in non heart failure hemodialysis patients. METHODS: Fourteen stable chronic hemodialysis patients (nine men), 59.5 ±â€Š3.1 years of age were evaluated in a sequential, fixed-dose, placebo-controlled study. Heart failure was diagnosed on the basis of signs and symptoms of heart failure or left ventricular ejection fraction less than 50%. Following an initial 4-month period of placebo administration after each dialysis, patients received spironolactone (25 mg thrice weekly after dialysis) for the next 4 months. Data were recorded at baseline, at the end of placebo administration, and at the end of spironolactone treatment and included endothelial function by forearm reactive hyperemia during venous occlusion plethysmography, cardiac autonomic status by heart rate variability in the time and frequency domain, blood pressure response, and echocardiographic and laboratory data. RESULTS: Placebo induced no changes in the aforementioned parameters. Following spironolactone, salutary effects were observed in the extent and duration of reactive hyperemia (P < 0.05 for both), as well as in heart rate variability (P < 0.05) and blood pressure control (P < 0.05). No changes occurred in echocardiographically derived left ventricular dimensions or mass. CONCLUSION: Low-dose spironolactone therapy in clinically stable non heart failure hemodialysis patients is associated with favorable effects on cardiovascular parameters known to adversely affect survival, such as endothelial dysfunction and heart rate variability. Spironolactone treatment might benefit long-term cardiovascular outcome of such patients.