A case of acute optic neuritis during pregnancy treated by membrane-based therapeutic plasma exchanges without systemic anticoagulation.

INTRODUCTION: In acute optic neuritis, high dose steroid therapy as first - line treatment is contraindicated in early pregnancy, therapeutic plasma exchanges (TPE) represent an alternative. We report a case of a pregnant woman with progressive, acute optic neuritis subjected to membrane-based therapeutic plasma exchange with extracorporal citrate-based anticoagulation. CASE PRESENTATION: A 35 year-old second-time pregnant woman (4th week of gravidity) of Caucasian ethnicity complained of visual impairment of the right eye. She was hospitalized for suspected optic neuritis. In the eye exam central and peripheral scotoma of the right side were found. T2 weighted Magnetic-Resonance Imaging revealed an isolated, prechiasmal lesion of the right optic nerve, and the patient had a delayed p100 latency of visually evoked potentials of the right eye. Cerebrospinal-fluid investigation was unrevealing. The diagnosis of right sided optic neuritis was established. Due to early pregnancy, steroids were contraindicated. Visual disturbances further deteriorated by day 2 in hospital. For therapy, 5 sessions of membrane-based therapeutic plasma exchange with albumin solution were performed. An extracorporal anticoagulation using citrate with calcium substitution was applied. After the second session, there was a subjective improvement of symptoms. At discharge on day 14, visual acuity was no longer impaired, sensitivity to bright light remained. In eye exam at 3.5 months after discharge, the patient ha d a complete recovery. Follow-up gynecological exams were unrevealing. CONCLUSION: This case of unilateral acute optic neuritis supports the view that membrane-based therpautic plasma exchange without systemic anticoagulation represents a safe intervention in pregnancy.

CD4+ T cell lymphopenia predicts mortality from Pneumocystis pneumonia in kidney transplant patients.

BACKGROUND: Pneumocystis jirovecii pneumonia (PcP) remains a life-threatening opportunistic infection after solid organ transplantation, even in the era of Pneumocystis prophylaxis. The association between risk of developing PcP and low CD4+ T cell counts has been well established. However, it is unknown whether lymphopenia in the context of post-renal transplant PcP increases the risk of mortality. METHODS: We carried out a retrospective analysis of a cohort of kidney transplant patients with PcP (n = 49) to determine the risk factors for mortality associated with PcP. We correlated clinical and demographic data with the outcome of the disease. For CD4+ T cell counts, we used the Wilcoxon rank sum test for in-hospital mortality and a Cox proportional-hazards regression model for 60-day mortality. RESULTS: In univariate analyses, high CRP, high neutrophils, CD4+ T cell lymphopenia, mechanical ventilation, and high acute kidney injury network stage were associated with in-hospital mortality following presentation with PcP. In a receiver-operator characteristic (ROC) analysis, an optimum cutoff of ≤200 CD4+ T cells/µL predicted in-hospital mortality, CD4+ T cell lymphopenia remained a risk factor in a Cox regression model. CONCLUSIONS: Low CD4+ T cell count in kidney transplant recipients is a biomarker for disease severity and a risk factor for in-hospital mortality following presentation with PcP.

Diabetes prevalence and outcomes in hospitalized cardiorenal-syndrome patients with and without hyponatremia.

BACKGROUND: Hyponatremia is known to be associated with a worse patient outcome in heart failure. In cardiorenal syndrome (CRS), the prognostic role of concomitant hyponatremia is unclear. We sought to evaluate potential risk factors for hyponatremia in patients with CRS presenting with or without hyponatremia on hospital admission. METHODS: In a retrospective study, we investigated 262 CRS patients without sepsis admitted to the University Hospital Halle over a course of 4 years. CRS diagnosis was derived from an electronic search of concomitant diagnoses of acute or chronic (NYHA 3-4) heart failure and acute kidney injury (AKIN 1-3) or chronic kidney disease (KDIGO G3-G5nonD). A verification of CRS diagnosis was done based on patient records. Depending on the presence (Na < 135 mmol/L) or absence (Na ≥ 135 mmol/L) of hyponatremia on admission, the CRS patients were analyzed for comorbidities such as diabetes, presence of hypovolemia on admission, need for renal replacement therapy and prognostic factors such as in-hospital and one-year mortality. RESULTS: Two hundred sixty-two CRS patients were included in this study, thereof, 90 CRS patients (34.4%) with hyponatremia (Na < 135 mmol/L). The diabetes prevalence among CRS patients was high (> 65%) and not related to the serum sodium concentration on admission. In comparison to non-hyponatremic CRS patients, the hyponatremic patients had a lower serum osmolality, hypovolemia was more prevalent (41.1% versus 16.3%, p < 0.001). As possible causes of hypovolemia, diarrhea, a higher number of diuretic drug classes and higher diuretic dosages were found. Hyponatremic and non-hyponatremic CRS patients had a comparable need for renal-replacement therapy (36.7% versus 31.4%) during the hospital stay. However, after discharge, relatively more hyponatremic CRS patients on renal replacement therapy switched to a non-dialysis therapy regimen (50.0% versus 22.2%). Hyponatremic CRS patients showed a trend for a higher in-hospital mortality (15.6% versus 7.6%, p = 0.054), but no difference in the one-year mortality (43.3% versus 40.1%, p = 0.692). CONCLUSIONS: All CRS patients showed a high prevalence of diabetes mellitus and a high one-year mortality. In comparison to non-hyponatremic CRS patients, hyponatremic ones were more likely to have hypovolemia, and had a higher likelihood for temporary renal replacement therapy.

Hyperglycemia-related central pontine demyelinization after a binge-eating attack in a patient with type-2 diabetes: a case report.

BACKGROUND: Here, we report a case of central pontine demyelinization in a type-2 diabetes patient with hyperglycemia after a binge-eating attack in the absence of a relevant hyponatremia. CASE PRESENTATION: A 55-year-old, male type-2 diabetic patient with liver cirrhosis stage Child-Pugh B was admitted due to dysmetria of his right arm, gait disturbance, dizziness, vertigo, and polyuria, polydipsia after a binge-eating attack of sweets (a whole fruit cake and 2 Liters of soft drinks). A recently initiated insulin therapy had been discontinued for 8 months. A serum glucose measurement obtained 5 days prior to hospitalisation was 38.5 mmol/l (694 mg/dl). The patient graved for sweets since stopping alcohol consumption 8 months earlier. On admission, venous-blood glucose was 29.1 mmol/l (523.8 mg/dl), glycated hemoglobin was 168.0 mmol/mol or 17.6%. No supplementation of sodium chloride was reported. Laboratory exams revealed an elevated serum ammonia level (127.1 µmol/l), rendering a hepatic encephalopathy very likely. After initiation of insulin therapy, capillary glucose normalized, and serum sodium rose from 133 on admission to 144 mmol/l during the hospital stay. In retrospect, the mild hyponatremia on admission was classified as pseudohyponatremia due to hyperglycemia. The patient had an insulin resistance (HOMA-IR 7.8 (normal range < 2.5)). A T2-weighted magnetic resonance imaging (MRI) of the head and a cranial computed tomography scan were obtained demonstrating a symmetric central pontine demyelinization. After 26 days in hospital, the patient was discharged with an inkretin-mimetic therapy (dulaglutide SC, 1.5 mg/week) and an intensified conventional insulin therapy (insulin aspart: 14 units/d in euglycemia, insulin glargin 20 units/d). CONCLUSIONS: Central pontine and/or cerebellar myelinolysis can be caused by sudden, severe, and sustained hyperglycemia, especially when another risk factor (in this case, liver cirrhosis) is present. Functional neurological deficits in the context of hyperglycemia should prompt for the consideration of this differential diagnosis in all diabetes patients.

How to Prevent Renal Cachexia? A Clinical Randomized Pilot Study Testing Oral Supplemental Nutrition in Hemodialysis Patients With and Without Human Immunodeficiency Virus Infection.

OBJECTIVE: End-stage renal disease associates with catabolism and sarcopenia. Hypothetically, peroral supplemental nutrition over 6 months prevents catabolism in hemodialysis patients. DESIGN: Prospective randomized pilot study (ClinicalTrials.gov Identifier: NCT00687050). SUBJECTS: Twenty-three hemodialysis patients (15 males and 7 females) with or without human immunodeficiency virus (HIV) infection of 2 ambulatory hemodialysis centers. INTERVENTION: HIV-positive hemodialysis patients (n = 7, Group 1) were started on supplemental nutrition drinks (250 kcal/day), HIV-negative hemodialysis patients (n = 16, Group 2) were randomized to supplemental nutrition drinks (250 kcal/day) or received none. MAIN OUTCOME MEASURES: Body impedance analysis, anthropometric measures, magnetic resonance imaging results for mid-iliopsoas muscle cross-sectional area and laboratory parameters including albumin, cytokines at baseline, and at 6 months follow-up. RESULTS: Seven patients in Group 1 (mean age: 50.6 ± 9.6 years) and 16 patients in Group 2 (mean age: 54.0 ± 13.3 years) were recruited. Serum creatinine (Group 1: 6.4 ± 3.0 mg/dL; Group 2: 10.7 ± 2.5 mg/dL; P < .01), Body impedance analysis-derived phase angle alpha (Group 1: 5.1 ± 1.2; Group 2: 6.9 ± 1.6; P < .01), mid-arm circumference (Group 1: 26.1 ± 1.3 cm; Group 2: 29.6 ± 2.4 cm; P < .01) were less in Group 1 versus Group 2 patients at baseline suggesting that HIV-positive hemodialysis patients had a poorer nutritional status at baseline. At 6-month follow-up, mortality was higher in Group 1 patients (29%) than in Group 2 patients (6%). There was no significant treatment effect on nutritional status in survivors of Group 1 or in the supplemental nutrition arm of Group 2 when compared with baseline or to untreated controls. CONCLUSIONS: A new oral supplemental nutrition over 6 months had no treatment effect in surviving HIV-positive hemodialysis patients or in maintenance hemodialysis patients without HIV infection. The limitations of this study were small study size and unexpected high mortality among HIV-positive hemodialysis patients.

Sympathoactivation and rho-kinase-dependent baroreflex function in experimental renovascular hypertension with reduced kidney mass.

BACKGROUND: Dysregulation of the autonomic nervous system is frequent in subjects with cardiovascular disease. The contribution of different forms of renovascular hypertension and the mechanisms contributing to autonomic dysfunction in hypertension are incompletely understood. Here, murine models of renovascular hypertension with preserved (2-kidneys-1 clip, 2K1C) and reduced (1-kidney-1 clip, 1K1C) kidney mass were studied with regard to autonomic nervous system regulation (sympathetic tone: power-spectral analysis of systolic blood pressure; parasympathetic tone: power-spectral analysis of heart rate) and baroreflex sensitivity of heart rate by spontaneous, concomitant changes of systolic blood pressure and pulse interval. Involvement of the renin-angiotensin system and the rho-kinase pathway were determined by application of inhibitors. RESULTS: C57BL6N mice (6 to 11) with reduced kidney mass (1K1C) or with preserved kidney mass (2K1C) developed a similar degree of hypertension. In comparison to control mice, both models presented with a significantly increased sympathetic tone and lower baroreflex sensitivity of heart rate. However, only 2K1C animals had a lower parasympathetic tone, whereas urinary norepinephrine excretion was reduced in the 1K1C model. Rho kinase inhibition given to a subset of 1K1C and 2K1C animals improved baroreflex sensitivity of heart rate selectively in the 1K1C model. Rho kinase inhibition had no additional effects on autonomic nervous system in either model of renovascular hypertension and did not change the blood pressure. Blockade of AT1 receptors (in 2K1C animals) normalized the sympathetic tone, decreased resting heart rate, improved baroreflex sensitivity of heart rate and parasympathetic tone. CONCLUSIONS: Regardless of residual renal mass, blood pressure and sympathetic tone are increased, whereas baroreflex sensitivity is depressed in murine models of renovascular hypertension. Reduced norepinephrine excretion and/or degradation might contribute to sympathoactivation in renovascular hypertension with reduced renal mass (1K1C). Overall, the study helps to direct research to optimize medical therapy of hypertension.

A case of granulomatosis with polyangiitis complicated by cyclophosphamide toxicity and opportunistic infections: choosing between Scylla and Charybdis.

BACKGROUND: We report a case of progressive Granulomatosis with Polyangiitis (Wegener's Granulomatosis) with life-threatening complications of both the underlying disease and induction immunosuppressive therapy. Here, for the first time, cyclophosphamide toxicity and severe opportunistic infections including pneumocystis jirovecii- pneumonia were found in one case in a close temporal relationship. CASE PRESENTATION: A 34-year-old male patient of Caucasian ethnicity presented with acute renal failure necessitating hemodialysis treatment due to Granulomatosis with Polyangiitis (Wegener's Granulomatosis). Kidney disease progressed to end-stage renal disease shortly after first diagnosis. After the 2nd bolus of cyclophosphamide shortly, induction immunosuppression (glucocorticoid/cyclophosphamide) was interrupted for repeat infections and resumed 5 years later. By that time, the lungs developed large pulmonary cavernae most likely due to smoldering granuloma indicative for the failed goal of disease remission. Therefore, induction immunosuppression was resumed. Following two monthly boli of cyclophosphamide, the patient developed pericardial effusion and, consecutively, atrioventricular blockade most likely due to cyclophosphamide. After recovery, the patient was discharged without cotrimoxacole. 10 weeks after the last cyclophosphamide bolus and 6 weeks after cessation of cotrimoxacole, the patient was readmitted to the intensive-care unit with Pneumocystis jirovecii pneumonia, and died 6 months later or 74 months after first diagnosis of Granulomatosis with Polyangiitis. CONCLUSIONS: This case illustrates both the need for adequate immunosuppressive therapy to reach disease remission and the limitations thereof in terms of complications including cardiotoxicity of cyclophosphamide and Pneumocystis jirovecii pneumonia. In line with current recommendations, the present case strongly encourages pneumocystis jirovecii- pneumonia chemoprophylaxis for at least 6 months following induction therapy in Granulomatosis with Polyangiitis.

Cardiorenal Syndrome: An Updated Classification Based on Clinical Hallmarks.

Cardiorenal syndrome (CRS) is defined as progressive, combined cardiac and renal dysfunction. In this mini review, a historical note on CRS is presented, the pathomechanisms and clinical hallmarks of both chronic heart failure and chronic kidney disease are discussed, and an updated classification of CRS is proposed. The current consensus classification relies on the assumed etiology and the course of the disease, i.e., acute or chronic CRS. Five types are described: type-I CRS presenting as acute cardiac failure leading to acute renal failure; type-II CRS presenting as chronic cardiac failure leading to chronic renal failure; type-III CRS presenting as acute kidney injury aggravating heart failure; type-IV CRS presenting as chronic kidney failure aggravating heart failure; and type-V CRS presenting as concurrent, chronic cardiac and renal failure. For an updated classification, information on the presence or absence of valvular heart disease and on the presence of hyper- or hypovolemia is added. Thus, CRS is specified as "acute" (type-I, type-III or type-V CRS) or "chronic" (type-II, type-IV or type-V) CRS, as "valvular" or "nonvalvular" CRS, and as "hyper-" or "hypovolemia-associated" CRS if euvolemia is absent. To enable the use of this updated classification, validation studies are mandated.

New Advances in Cardiorenal Syndrome-Ready for Prime Time?

Cardiorenal Syndrome has become one pressing issue as far as hospitalizations are concerned [...].

Experimental uninephrectomy associates with less parasympathetic modulation of heart rate and facilitates sodium-dependent arterial hypertension.

BACKGROUND: Blood pressure is known to be increased in kidney donors following living-donor kidney transplantation. However, the physiological underpinnings of the blood-pressure increase following uninephrectomy remain unclear. We hypothesized that changes in sympathetic tone or in parasympathetic modulation of sinus node function are involved in the blood-pressure increase following experimental kidney-mass reduction. METHODS: C57BL6N mice (6 to 11 per group) subjected to sham surgery (controls) or uninephrectomy with or without a one-week course of sodium chloride-enriched, taurine-deficient diet were studied. Uninephrectomized mice treated with a subcutaneous infusion of angiotensin-II over a period of one week were positive controls. A transfemoral aortic catheter with telemetry unit was implanted, readings of heart-rate and blood-pressure were recorded. Powerspectral analysis of heart rate and systolic blood pressure was performed to gain surrogate parameters of sympathetictone and parasympathetic modulation of sinus node function. Baroreflex sensitivity of heart rate was determined from awake, unrestrained mice using spontaneous baroreflex gain technique. RESULTS: Systolic arterial blood pressure, heart rate and baroreflex sensitivity were not different in uninephrectomized mice when compared to controls. Parasympathetic modulation of sinus node function was less in uninephrectomized mice in comparison to controls. Uninephrectomized mice of the high-angiotensin-II model or of the high-salt and taurine-deficiency model had an increased systolic arterial blood pressure. CONCLUSIONS: Uninephrectomy associated with less parasympathetic modulation of sinus node function. The combination of uninephrectomy, taurine-deficiency and high-salt intake led to arterial hypertension.

Therapeutic Plasma Exchanges in Combination with High-Dose Steroid-Induced Immunosuppression as an Ultima Ratio Therapy in Severe Coronavirus Disease 2019 (COVID-19): A Case-Series Report.

We present 2 cases of severe Covid-19 with comorbidities (arterial hypertension, obesity, diabetes mellitus) treated with membrane-based therapeutic plasma exchanges in combination with a short-term high-dose immunosuppressive therapy. The therapy has been initiated in an attempt to alleviate the prevalent cytokine storm and to prevent intubation and invasive mechanical ventilation, when a long-term nasal oxygen therapy with a maximum flow rate of 8L/min was insufficient to achieve an adequate oxygenation. Even though patient 2 had to be intubated after the 4th cycle of plasmapheresis due to the exhaustion of the respiratory muscles and the subsequent acquired sepsis with a microbiological evidence of a mixed bacterial-fungal infection, both patients showed a good response to treatment, including improvement of laboratory and radiological findings. To our knowledge, this combination of therapeutic plasma exchange with a high-dose steroid therapy has not been reported previously.

Risk factors for Pneumocystis jiroveci pneumonia (PcP) in renal transplant recipients.

BACKGROUND: Pneumocystis jiroveci pneumonia (PcP) is a potentially life-threatening complication in renal transplant recipients with increased reports during the past few years. Individual risk factors for susceptibility to PcP are incompletely understood. METHODS: We retrospectively analysed 60 cases of confirmed PcP, diagnosed in six German transplant centres between 2004 and 2008, as well as 60 matched controls. RESULTS: Compared with controls, PcP cases revealed the following significant differences: PcP cases had a poorer renal function (eGFR 31 vs. 42 mL/min in controls), more biopsy-proven rejections (18 vs. 5 patients), more frequent treatment with mycophenolate mofetil (53 vs. 44 patients) and less frequent treatment with interleukin-2 receptor antagonist (20 vs. 32 patients). According to centre policy, in those years, none of the patients or controls had received PcP prophylaxis after transplantation. Of the 60 patients with PcP, 30% developed the disease after the currently recommended duration of prophylactic treatment, 27% died in the course of the disease and 45% required treatment in the ICU. CONCLUSIONS: Our case-control study reveals a novel risk profile for PcP. Renal transplant recipients with more pronounced renal insufficiency following rejection episodes and treated with intensified immunosuppression are at particular risk for PcP.

Renal allograft-related inflammation complicated by acute coronary syndromes: A case report.

INTRODUCTION: Persistent systemic inflammation is considered to be predictive for future cardiovascular events. Here, in a patient with pyelonephritis of his failed renal allograft, consecutive coronary angiograms proved that coronary artery disease progressed within 3 weeks, when infection was uncontrolled. PATIENT CONCERNS: A 52-year-old male type 2 diabetic with a failed renal allograft suffering from hematuria, leukocyturia, and chest pain at rest was hospitalized. DIAGNOSES: An acute coronary syndrome in presence of pyelonephritis was diagnosed. Besides pyelonephritis, the histological examination of the kidney transplant revealed signs of chronic rejection and the presence of a renal cell carcinoma in situ. INTERVENTIONS: A percutaneous coronary intervention was performed, and an elective surgery for allograft removal was scheduled. However, within 5 weeks after discharge, two more surges of infection coincided with episodes of unstable angina. OUTCOMES: Once the renal allograft has been removed, systemic inflammation was contained. The patient was not re-hospitalized for acute-coronary syndrome within the next 12 months. CONCLUSION: Surges of systemic inflammation due to infection were paralleled by instability of coronary plaques as documented by repeat coronary angiograms.

Prevalence of Incretin-Mimetic and Sodium-Glucose-Transporter-2-Inhibitor Therapy in German Hospitalized Type-2 Diabetics Following Myocardial Revascularization: An Observational Study.

INTRODUCTION: Real-world data indicate that sodium glucose transporter-2-inhibitor therapy and/or incretin mimetics are not widely prescribed in type-2 diabetics with atherosclerotic vascular disease. We hypothesized that incretin-mimetic therapy is associated with better overall survival and 1-year mortality in type-2 diabetics following myocardial revascularization. METHODS: Hospitalized type-2 diabetics of the Departments of Cardiology and Cardiothoracic Surgery (University Hospital Halle) who needed myocardial revascularization (PCI or CABG) in 2016 were included in this observational study: group 1 (incretin-mimetic therapy), group 2 (insulin therapy without incretin mimetics) and group 3 (oral diabetes medication without incretins or insulin). They were asked to mail in a questionnaire on medical therapy and outcomes 1.9 years following discharge. In non-responders, vital status was obtained by local registration offices 2.4 years after discharge. RESULTS: Two hundred four patients were recruited in this study. At discharge, only 4.4% of all type-2 diabetics were on incretin mimetic, 39.7% on insulin and 55.9% on oral diabetes medication. At the time of follow-up (response rate: 44.1%), there was no change in terms of prevalence of incretin-mimetic therapy (5.6% of responders). Prevalence of sodium glucose transporter-2-inhibitor therapy increased from 6.9% to 15.6% in responders. In-hospital mortality (group 1: 0%, group 2: 0%, group 3: 5.2%; p = 0.092), survival after discharge (group 1: 88.9%, group 2: 86.4%, group 3: 88.0%; p = 0.942) and number of rehospitalizations within 12 months after discharge (group 1: 1.0 per capita, group 2: 1.0, group 3: 1.1; p = 0.697) were similar among prespecified groups and between group 2 and 3. By 1.9-year follow-up, hypoglycemic events were more frequent in group 2 (1.5 ± 2.9) than in group 3 (0.02 ± 0.1; p = 0.0001). CONCLUSION: The prevalence of incretin mimetics and sodium-glucose-transporter-2 inhibitors was low both during the index hospitalization and at a 1.9-year follow-up. When comparing group 2 and group 3 patients, survival and rehospitalizations were similar; hypoglycemic events occurred more often in insulin-treated diabetics than in the those without.

Glycopenia - induced sympathoadrenal activation in diabetes mellitus and uncontrolled arterial hypertension: an observational study.

BACKGROUND: Aim of this study is to investigate a possible association of hypoglycemic episodes and arterial hypertension. We hypothesize that hospitalized insulin-treated diabetes patients with hypertensive crisis have more hypoglycemic episodes than their counterparts without hypertensive crisis on admission. METHODS: In a prospective, observational cohort study, 65 insulin-treated diabetes patients (type 1, type 2, type 3c) were included in Group 1, when a hypertensive crisis was present, as control patients in Group 2 without hypertensive crisis or hypoglycemia, in Group 3, when a symptomatic hypoglycemia was present on admission. All patients were subjected to open-label continuous glucose monitoring, 24-h blood-pressure- and Holter electrocardiogram recordings, and to laboratory tests including plasma catecholamines. RESULTS: 53 patients, thereof 19 Group-1, 19 Group-2, 15 Group-3 patients, completed this study. Group-1 patients had the highest maximum systolic blood pressure, a higher daily cumulative insulin dose at admission, a higher body-mass index, and a higher plasma norepinephrine than control patients of Group 2. Group-3 patients had more documented hypoglycemic episodes (0.8 ± 0.5 per 24 h) than Group-2 patients (0.2 ± 0.3 per 24 h), however, they were not different to the ones in Group-1 patients (0.4 ± 0.4 per 24 h). Plasma norepinephrine and mean arterial blood pressure were higher Group-1 and Group-3 patients than in control patients of Group 2. At discharge, the daily cumulative insulin dose was reduced in Group-1 (- 18.4 ± 24.9 units) and in Group-3 patients (- 18.6 ± 22.7 units), but remained unchanged in Group-2 control patients (- 2.9 ± 15.6 units). CONCLUSIONS: An association between hypoglycemic events and uncontrolled hypertension was found in this study.

Altered gene expression pattern indicates the differential regulation of the immune response system as an important factor in cardiac aging.

Numerous changes occur in the old myocardium which finally cause lower cardiac output and, therefore, circulatory dysfunction. In order to identify an age-related gene expression pattern, we analyzed left ventricular myocardium of adult (6 months) and old (24 months) mice by use of whole genome expression arrays. About 2.3% of genes expressed above the median value of all genes were differentially expressed in old hearts. Nearly all of them were upregulated. After application of defined exclusion criteria, 98 genes were selected for a more detailed analysis. About one third of the 98 genes codes for factors involved in the immune reaction, such as chemokines (CCLs 6, 8, 9), proteins of the S100 family (S100s 4, 8, 9, 10, 11), complement components (C1qa, C1qb, C1qc, C3, C4b), bacteria/virus-induced genes (lysozyme 1/2, interferon-activated genes), and pro-inflammatory caspases (Casp1, Casp4, Casp12). Predominantly, genes coding for factors of the immune reaction were simultaneously upregulated in the kidneys and lungs of old mice, thereby emphasizing the pivotal role of immune cells in tissue aging. In conclusion, myocardial aging is mainly associated with an altered expression pattern of molecules involved in the immune reaction.

Systemic inflammation in acute cardiorenal syndrome: an observational pilot study.

AIMS: Acute cardiorenal syndrome (CRS) with and without consideration of the volume state was assessed with regard to inflammatory parameters. METHODS AND RESULTS: Blood samples from patients with acute CRS (Ronco type 1 or 3, Group 1, n = 15), end-stage renal disease (Group 2, n = 12), hypertension (Group 3, n = 15), and, in a second cohort, with acute CRS and hypervolemia (Group 4, n = 9) and hypertension (Group 5, n = 10) were analysed with regard to lipopolysaccharide-binding protein (LBP), interleukins (ILs), and monocyte function (flow cytometry) both on admission (all groups) and on discharge (Groups 1 and 4). By discharge, one Group 1 patient died. LBP (ANOVA for Groups 1-3: P = 0.001) and IL-6 (Kruskal-Wallis for Groups 1-3: P < 0.0001) were higher in Group 1 (LBP: 11.7 ± 2.0 µg/mL; IL-6: 15.0 ± 6.1 pg/mL) and in Group 2 (LBP: 10.4 ± 1.4 µg/mL; IL-6: 14.6 ± 3.8 pg/mL) than in Group 3 (LBP: 5.8 ± 0.4 µg/mL; IL-6: 1.8 ± 0.4 pg/mL). In a direct comparison, the proportion of activated monocytes (CD14 and CD16 positive) was higher in Group 1 (6.9% ± 0.7%) vs. Group 3 (5.1% ± 0.6%; P = 0.018). Group 4 patients had higher IL-6 plasma levels (34.2 ± 10.1 pg/mL) than Group 1 patients (15.0 ± 6.1 pg/mL; P = 0.03). All other findings obtained in CRS groups (Groups 1 and 4) were comparable. CONCLUSIONS: In acute CRS, a state of systemic inflammation was found, which is comparable with the end-stage renal disease situation. In comparison with hypertensive controls, a monocytic activation was found in acute CRS regardless of volume state.

Urinary Proteolytic Activation of Renal Epithelial Na+ Channels in Chronic Heart Failure.

One of the key mechanisms involved in renal Na(+) retention in chronic heart failure (CHF) is activation of epithelial Na(+) channels (ENaC) in collecting tubules. Proteolytic cleavage has an important role in activating ENaC. We hypothesized that enhanced levels of proteases in renal tubular fluid activate ENaC, resulting in renal Na(+) retention in rats with CHF. CHF was produced by left coronary artery ligation in rats. By immunoblotting, we found that several urinary serine proteases were significantly increased in CHF rats compared with sham rats (fold increases: furin 6.7, prostasin 23.6, plasminogen 2.06, and plasmin 3.57 versus sham). Similar increases were observed in urinary samples from patients with CHF. Whole-cell patch clamp was conducted in cultured renal collecting duct M-1 cells to record Na(+) currents. Protease-rich urine (from rats and patients with CHF) significantly increased the Na(+) inward current in M-1 cells. Two weeks of protease inhibitor treatment significantly abrogated the enhanced diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. Increased podocyte lesions were observed in the kidneys of rats with CHF by transmission electron microscopy. Consistent with these results, podocyte damage markers desmin and podocin expressions were also increased in rats with CHF (increased ≈2-folds). These findings suggest that podocyte damage may lead to increased proteases in the tubular fluid, which in turn contributes to the enhanced renal ENaC activity, providing a novel mechanistic insight for Na(+) retention commonly observed in CHF.

Simvastatin normalizes autonomic neural control in experimental heart failure.

BACKGROUND: HMG-CoA reductase inhibitors (statins) have been shown to beneficially affect outcomes in chronic heart failure (CHF). We hypothesized that statins exert effects on autonomic function, as assessed by plasma norepinephrine levels, direct recordings of renal sympathetic nerve activity (RSNA), and baroreflex function. METHODS AND RESULTS: Normolipidemic CHF rabbits were treated with simvastatin or vehicle. CHF was induced by continuous ventricular pacing at 320 to 340 bpm for 3 weeks. Two to 3 days after instrumentation of the rabbits with renal nerve electrodes and arterial and venous catheters, blood samples and RSNA recordings were obtained in the conscious state. Baroreflex function was assessed after administration of sodium nitroprusside and phenylephrine. Mean baseline RSNA (+/-SEM) in normal rabbits was 19.3+/-3.8%; in CHF rabbits, 39.4+/-2.9% (P<0.05); in CHF rabbits on low-dose (0.3 mg x kg(-1) x d(-1)) simvastatin, 39.8+/-8.3% (P<0.05); and in CHF rabbits on high-dose simvastatin (3 mg x kg(-1) x d(-1)), 21.1+/-4.5% (P=NS). Similar data were observed for plasma norepinephrine. In CHF rabbits treated with 3 mg x kg(-1) x d(-1) simvastatin, baroreflex regulation of heart rate to transient hypotension with sodium nitroprusside was normalized by 66% compared with CHF controls. CONCLUSIONS: These are the first data showing that non-lipid-lowering statin effects include a normalization of sympathetic outflow and reflex regulation in CHF. The precise neural and cellular pathways involved in these responses need further clarification. This finding may have important implications for the treatment of CHF and progression of the disease process.