Parasympathetic activity increases with digital microvascular damage and vascular endothelial growth factor in systemic sclerosis.

OBJECTIVES: The imbalance between angiogenic and angiostatic factors with derangement of the microvasculature are hallmarks of systemic sclerosis (SSc). Raynaud's phenomenon in SSc probably is due to the impaired neuroendothelial control mechanisms between vasoconstriction and vasodilatation. The aim of this study is to evaluate autonomic nervous system function using heart rate variability (HRV) analysis and to correlate with vascular endothelial growth factor (VEGF). METHODS: Twenty-seven SSc patients were enrolled. HRV was measured and markers of global sympathetic and parasympathetic system, respectively standard deviation of normal-to-normal RR intervals (SDNN) and square root of the mean of the sum of the squares of differences between adjacent NN intervals (RMSSD) were evaluated. Serum VEGF levels and nailfold videocapillaroscopy (NVC) were performed. RESULTS: A linear positive correlation was observed between RMSSD and VEGF (p<0.01, r=0.55), and RMSSD and disease duration (p< 0.01, r=0.54). The RMSSD median value was significantly increased (p< 0.05) with NVC damage progression. The RMSSD median value was significantly (p<0.05) higher in SSc patients with digital ulcers (DUs) than in SSc patients without DUs [44 (39.4-60.2) vs 24.6 (23-37.1)]. CONCLUSIONS: In our study parasympathetic modulation increases in relation to VEGF. When microcirculation is modified with capillaroscopic pattern progression and DUs, autonomic system seems to stimulate vasodilatation trough parasympathetic system. We can conclude that parasympathetic activity increases with digital microvascular damage and promotes VEGF release.

Effects of autonomic dysfunction on exercise tolerance in systemic sclerosis patients without clinical and instrumental evidence of cardiac and pulmonary involvement.

OBJECTIVES: Autonomic dysfunction (AD) in systemic sclerosis (SSc) was already confirmed through heart rate variability (HRV) analysis. Cardio-pulmonary exercise testing (CPET) is a useful tool in early detection of exercise tolerance in SSc patients. Aim of the study was to assess the relationships existing between AD and exercise tolerance. METHODS: Thirty-two [4 M, 28 F; median age: 47.5 (20-65) years] consecutive SSc patients were enrolled. All patients underwent pulmonary function testing, incremental symptom-limited CPET and twenty-four hours ECG Holter recording with HRV analysis in time and frequency domain. Multiple regression analysis was performed in order to identify independent HRV predictors of exercise tolerance and cardiac efficiency during the effort. RESULTS: HRV analysis showed significant differences in power in low and high frequency (LF and HF, respectively) and their ratio (LF/HF) compared to healthy controls. Nocturnal ratio be- tween power in low and high frequency at HRV (LF/HFnight) was shown to be the only independent positive predictor of maximal work load (R2=18.6%, p=0.014) and maximal oxygen consumption (V' O2 peak) expressed both as absolute value (R2=24.2%, p=0.004) and as corrected for body weight (R2=21.6%, p=0.007). A positive linear relationship was also found between nocturnal LF (LFnight) and the oxygen uptake/work rate (V'O2/W) slope (R2=15.8%, p=0.024). CONCLUSIONS: In SSc patients without cardiopulmonary involvement AD is associated with better exercise tolerance and cardiac function during physical effort. Further studies are needed to confirm these results.

Gabexate mesylate as treatment in the course of ANCA-negative microscopic polyangiitis.

Patients with small vessel vasculitis present fluctuating antineutrophil cytoplasmic antibodies (ANCA) levels to the point that positive ANCA may be missed even if only up to 10% of patients with microscopic polyangiitis (MPA) are ANCA-negative. The first-line treatment of MPA is the association of steroids and cyclophosphamide, especially in the presence of a rapidly progressive glomerulonephritis. Plasmapheresis, intravenous immunoglobulins, and tumor necrosis factor inhibitors have been proposed as alternative to standard therapy. Disseminated intravascular coagulation (DIC) is a possible event in the course of small vessel vasculitis. Gabexate mesylate is a protease inhibitor able to suppress endothelial cell injury, and it may be administered to treat DIC related to different diseases. In ANCA-associated vasculitis, cytokines play a key role in promoting endothelial damage. DIC-related thrombocytopenia may be misinterpreted as drug-induced because of the immunosuppressive properties of cyclophosphamide. Two cases of ANCA-positive MPA associated with DIC and treated with gabexate are reported in the literature with improvement of both hematological disorder and renal function. Our patient presented a rapidly progressive glomerulonephritis, and the renal biopsy showed MPA, in the absence of ANCA. After two weeks of steroid treatment, our patient developed a DIC. This case represents the first report of ANCA-negative MPA managed with gabexate, which showed improvement of coagulation disorders and kidney function. In conclusion, the anti-inflammatory properties of gabexate could be helpful in MPA at increased bleeding risk when immunosuppressive treatment is contraindicated, even in ANCA-negative vasculitis.

Role of autonomic dysfunction in the regulation of myocardial blood flow in systemic sclerosis evaluated by cardiac magnetic resonance.

AIM: Autonomic dysfunction (AD) is an early feature of systemic sclerosis (SSc). A regular endothelial function is a prerequisite for normal response of the myocardial blood flow (MBF) to cold pressure test (CPT). The aim of the study was to evaluate the relation between MBF and AD at rest and after CPT in asymptomatic SSc patients. METHODS: Twenty SSc patients and 10 age-, sex- and body mass index-matched healthy controls underwent cardiac magnetic resonance at rest and after CPT. All subjects underwent 24 hours ambulatory 3-channel electrocardiogram Holter to evaluate AD by heart rate variability. RESULTS: We did not observe any significant difference in MBF (mL/g/min) at rest and after CPT between SSc patients and healthy controls. Delta of MBF (difference between MBF after CPT and rest MBF) was lower (P = 0.039) in SSc patients than healthy controls (0.28 [0.04-0.40] vs 0.33 [0.24-0.54]). The low frequency/high frequency (LF/HF) was higher (P = 0.002) in SSc patients than healthy controls (3 [1.7-6] vs 1.8 [1.1-2.8]). The high frequencies (HF), modulated mainly by paraympathetic system, was lower (P = 0.003) in SSc patients than healthy controls (30 [16-42] vs 36.5 [24-44]). Sympathetic hyperactivity, due to reduction of parasympathetic activity (HF), is present in SSc patients. A negative correlation was observed between Delta of MBF and LF/HF (r = -0.572, P = 0.0031). CONCLUSION: AD, characterized by sympathovagal imbalance due to a reduced parasympathetic tone with high LF/HF ratio, could be responsible for the reduced myocardial vasodilatory response after CPT.

The involvement of T regulatory lymphocytes in a cohort of lupus nephritis patients: a pilot study.

T regulator lymphocytes (Tregs) play a key role in the maintenance of immune tolerance and in the development of autoimmune diseases. Expression of Foxp3 is specific for Tregs, and can be used for the identification of these cells. This study investigated the variations of Tregs Foxp3+ in the kidney biopsies inflammatory infiltrate of different lupus nephritis classes compared to that of ANCA glomerulonephritis, acute tubulointerstitial nephritis and nephroangiosclerosis. Sections of paraffin-embedded tissue have been stained by immunohistochemistry with anti-CD3 and anti-FoxP3 antibodies. We find that the ratio of FoxP3+/CD3+ cells is significantly lower in patients with lupus nephritis class IV and in patients with vasculitides than in the course of nephroangiosclerosis, tubulointerstitial nephritis and lupus nephritis class V. The data presented herein demonstrate a decrease of FoxP3+ Treg cells in the inflammatory infiltrate of lupus nephritis, particularly during the most active phases of lupus nephritis, as observed in the course of a IV class nephritis.

Drugs and Rhabdomyolysis: From Liver to Kidney.

Rhabdomyolysis is a syndrome due to a damage of skeletal muscle and the leakage of intracellular contents into the extracellular fluid and the circulation. Several causes may induce rhabdomyolysis and the major one is the crush syndrome. Most cases of non-traumatic rhabdomyolysis are related to drugs. Many molecules are subject to hepatic metabolism and the concomitant use of drugs, as statins, with other medications acting as substrates of the same isoenzymes can interact and increase the risk of myopathy. Subclinical rise of creatine kinase may be the expression of rhabdomyolysis that can present as a medical emergency such as acute kidney injury (AKI), compartment syndrome, cardiac dysrhythmias and disseminated intravascular coagulopathy. The main pathophysiological mechanisms of myoglobinuric-related AKI are renal vasoconstriction, formation of intraluminal casts and direct cytotoxicity promoted by heme-protein. The aim of this review is to analyze the pathophysiology of myolysis, the causes of rhabdomyolysis and especially the link between the liver and the kidney, which can represent the connecting element for the development of the syndrome.

Prevalence and clinical features of patients with the cardiorenal syndrome admitted to an internal medicine ward.

BACKGROUND: Many patients admitted to a Department of Internal Medicine have different degrees of heart and kidney dysfunction. Mortality, morbidity and cost of care greatly increase when cardiac and renal diseases coexist. METHODS: A retrospective cohort study was conducted on 1,087 patients admitted from December 2009 to December 2012 to evaluate the prevalence of the cardiorenal syndrome (CRS) and clinical features. RESULTS: Out of 1,087 patients discharged from our unit during the study period, 190 (17.5%) were diagnosed as having CRS and classified into five types. CRS was more common in males (68.9%). CRS type 1 was associated with higher age (79.9 ± 8.9 years) and accounted for 61.5% of all deaths (p < 0.001), representing a risk factor for mortality (OR 4.23, 95% CI 1.8-10). Congestive heart failure was significantly different among the five CRS types (p < 0.0001) with a greater frequency in type 1 patients. Infectious diseases were more frequent in CRS types 1, 3 and 5 (p < 0.05). Pneumonia presented a statistically higher frequency in CRS types 1 and 5 compared to other classes (p < 0.01), and community-acquired infections were statistically more frequent in CRS types 1 and 5 (p < 0.05). The distribution of community-acquired pneumonia was different among the classes (p < 0.01) with a higher frequency in CRS types 1, 3 and 5. CONCLUSION: CRS is a condition that is more frequently observed in the clinical practice. The identification of predisposing trigger factors, such as infectious diseases, particularly in the elderly, plays a key role in reducing morbidity and mortality. An early recognition can be useful to optimize therapy, encourage a multidisciplinary approach and prevent complications.

Hypercoagulability and nephrotic syndrome.

Patients with nephrotic syndrome are at increased risk for thromboembolic events such as deep venous and arterial thrombosis, renal vein thrombosis and pulmonary embolism. This thrombophilic phenomenon has been attributed to a "hypercoagulable" state in which an imbalance between naturally occurring pro-coagulant/pro-thrombotic factors and anti-coagulant/antithrombotic factors promotes in situ thrombosis in deep veins or arteries. Management of thromboembolic events may be divided in prophylactic and therapeutic strategies. Hypoalbuminemia is the most significant independent predictor factor of thrombotic risk, especially for values <2 g/dL. However, the most important question in these patients is whether to anticoagulate prophylactically or not. The decision depends on type of glomerulonephritis, proteinuria severity, other predisposing factors and prior history of thrombosis. Reviewing the recent literature, we suggest the best therapeutic management of anticoagulation for patients with nephrotic syndrome, focusing on prophylactic strategies.

Pathophysiology, diagnosis and clinical management of hepatorenal syndrome: from classic to new drugs.

Advanced cirrhosis is frequently associated with renal dysfunction. Hepatorenal syndrome (HRS) is characterized by the occurrence of kidney injury in cirrhotic patients in the absence of other identifiable causes. HRS is classified in 2 different types. Type 1 is characterized by acute renal failure and rapid functional deterioration of other organs, usually related to a precipitating event. Type 2 is characterized by slowly progressive renal failure and refractory ascites. Advanced liver disease induces the progression of hemodynamic alterations such as arterial vasodilation of splanchnic circulation and impairment of cardiac function. The resulting ineffective circulating blood volume promotes the activation of both the renin-angiotensin-aldosterone and sympathetic nervous system, by an increase of antidiuretic hormone activity, in an attempt to restore volemia. Despite fluid retention, ascites and dilutional hyponatremia, renal function is often initially preserved by renal production of vasodilators. However, further insults can lead to an imbalance between systemic vasoconstriction and local renal vasodilation, resulting in progressive renal failure. Over the last decade, clinical strategies to prevent HRS have been improved by a better understanding of the natural history of renal failure in cirrhosis, resulting in a reduction of HRS prevalence in cirrhotic patients. Vasoconstrictor drugs may improve renal function, but the effect on mortality has not yet been established. Vaptans, nonpeptide vasopressin receptor antagonists, may also reduce hyponatraemia and ascites, even if the clinical effects in HRS remain unknown. This review updates the pathophysiology, diagnosis and management of HRS.

Rhabdomyolysis after midazolam administration in a cirrhotic patient treated with atorvastatin.

The administration of statins in patients with liver disease is not an absolute contraindication. Hepatotoxicity is a rare and often dose-related event and in the literature there are only a few described cases of fatal rhabdomyolysis in patients with chronic liver disease after statin administration. During treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, the factors responsible for myopathy may either be related to the patient, or due to interactions with other medications that are metabolic substrates of the same isozymes and therefore able to increase blood statin concentration. The most important side effects consist of increased transaminase levels, abdominal pain or muscle weakness, increased serum levels of creatine kinase and rhabdomyolysis. In this article we report a case of fatal rhabdomyolysis with acute renal failure after gastric endoscopy, where midazolam was used as a sedation agent in a patient with chronic liver disease treated with a high dose of atorvastatin. Therefore, we suggest paying particular attention to the potential risks of associating atorvastatin and midazolam in patients with chronic liver disease who need to undergo gastric endoscopy.