Liborio Sardo

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.

Autonomic dysfunction in patients with systemic sclerosis: Correlation with intrarenal arterial stiffness

Systemic sclerosis (SSc) is a systemic disease of connective tissue,characterized by endothelial dysfunction and fibrosis of the skin andvisceral organs [1]. Autonomic dysfunction (AD) is a feature of SSc,starting early in the disease and possibly preceding the developmentof fibrosis [2].Several manifestations of renal involvement occur in SSc and wehave recently demonstrated that renal resistive index (RI) correlateswith glomerular filtration rate (GFR), digital microvascular damage [3]and in monitoring scleroderma renal crisis [4].Accordingly, the aim of the study is to assess intrarenal arterialstiffness by Doppler ultrasound and examine the correlation with ADusing heart rate variability (HRV) analysis.The protocol is in accordance with the Declaration of Helsinki andwas approved by the Ethics Committee at our Institution. NineteenCaucasian subjects fulfilling the American Rheumatism Association(ARA) criteria for classification and diagnosis of SSc [5] and nineteenhealthysubjectswereexaminedbeforeinclusioninthestudy.Allexam-ined patients underwent clinical evaluation, 24-h Holter monitoring,electrocardiography (ECG) and transthoracic echocardiogram.Scleroderma patients with coronary artery disease, congestiveheartfailure, left ventricular dysfunction, significant valvular abnormalitiesand arrhythmias were not included in the study.Patients with pulmonary function abnormalities were not includedeither. Patients with diabetes mellitus, renal failure, hepatic or thyroiddysfunction and anaemia were excluded.Patients were not taking β-blockers, antiarrhythmic drugs, ACE-inhibitors or angiotensin receptor antagonists. GFR was calculatedwith CKD-EPI equation [6].Autonomic nervous activity was evaluated by heart rate variability(HRV) analysis during 24-hour ECG recording. Autonomic nervousactivity was analyzed following the recommendations of the TaskForce of the European Society of Cardiology and the North AmericanSociety of Pacing and Electrophysiology [7]. Total power in the fre-quency range (0–0.40 Hz) was divided into low frequency (LF:0.04–0.15 Hz, modulated mainly by sympathetic system) and highfrequency (HF: 0.15–0.40 Hz, modulated by parasympathetic system).The power of LF and HF components was considered in normalizedunits (nu). LF/HF rate is sympathovagal balance. Artificial data andarrhythmic were excluded. Data analyses were performed with soft-ware Del Mar Avionics Accuplus 363, Irvine California, USA.Renal Doppler ultrasound was performed using a Toshiba AplioUltrasound System SSA-790 (Tokyo, Japan) equipped with convex 3.5-MHz probe. RI was calculated as (peak systolic frequency shift −minimum diastolic frequency shift) / peak systolic frequency shift.All the ultrasound examinations were performed by same blindedphysician in order to reduce variability in the assessment managementof the study.Thedatawereexpressedasmedianandrange.Multivariateanalysiswas applied for the estimation of relationship of HRV variables withrenal Doppler indices or disease variables. The Mann–Whitney U-testor Kruskal–Wallis was used to test differences between two individualstudy groups. Spearmans rank order correlation coefficient (r) wasused to test for an association between numerical variables. p-Valuesb0,05 were considered significant. Commercially software (SPSSversion 20.0) was used for statistical analysis.Nineteen scleroderma patients were enrolled in the current study.Median age of 45 years (range 23–58) and a median SSc duration of6,5 years (range 2–25) were investigated in the Clinical ImmunologyUnit-Scleroderma Center. Six patients had limited cutaneous SSc and

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.

D-Lactic acidosis 25 years after bariatric surgery due to Salmonella enteritidis

D-Lactic acidosis is a rare complication that occurs in patients with short bowel syndrome due to surgical intestine resection for treatment of obesity. The clinical presentation is characterized by neurologic symptoms and high anion gap metabolic acidosis. The incidence of this syndrome is unknown, probably because of misdiagnosis and sometimes symptoms may be incorrectly attributed to other causes. Therapy is based on low carbohydrate diet, sodium bicarbonate intravenous, rehydratation, antiobiotics, and probiotics that only produce L-lactate. In the case we describe, D-lactic acidosis encephalopathy occurred 25 y after bypass jejunoileal, due to Salmonella enteriditis infection.

Intrarenal hemodynamic and oxidative stress in patients with obstructive sleep apnea syndrome

BackgroundOxygen desaturation and reoxygenation, related to intermittent hypoxia cycles due to upper airway obstruction, are major pathophysiologic features of obstructive sleep apnea syndrome (OSAS) and are thought to be responsible for an increased risk of cardiovascular diseases. Continuous positive airway pressure (CPAP) is therefore considered the gold standard in the management of OSAS. Further data demonstrated a high prevalence of OSAS in patients with altered renal function despite the underlying pathophysiological mechanisms that have not been clarified. This study aims to provide evidence on the reported high prevalence of endothelial dysfunction and alterations of the intrarenal hemodynamic in patients affected by OSAS. Furthermore, we evaluated the effect of a CPAP therapy on these endpoints.MethodsTwenty patients were enrolled in a prospective study and underwent ultrasound examination to assess endothelial dysfunction, by collecting brachial flow-mediated dilation (FMD) and intrarenal artery stiffness, pre- and post a 30-day treatment with CPAP.ResultsEndothelial dysfunction and intrarenal artery stiffness significantly improved in all patients after a month of CPAP. In particular, we observed a significant reduction in the renal resistance index (RI) (p < 0.001) and systolic/diastolic ratio (S/D) ratio (p < 0.001) and a significant increase of FMD (p < 0.001). The apnea-hypopnea index (AHI) showed a negative correlation with Δ FMD (p < 0.05, r = −0.46). Conversely, a positive correlation exists between Δ RI and the oxygen desaturation index (ODI) (specificare la sigla) (p < 0.05, r = 0.46).ConclusionsOur study firstly showed a significant effect of CPAP on renal perfusion and endothelial function in OSAS patients without concomitant cardiovascular comorbidities.

QTc interval prolongation in systemic sclerosis: Correlations with clinical variables

Systemic sclerosis (SSc) is an autoimmune disease characterized byendothelial dysfunction and fibrosis of the skin and internal organs [1].Cardiac involvement in the course of SSc could be primary or sec-ondary to pulmonary arterial hypertension and kidney pathology. Pri-mary cardiac involvement may manifest as myocardial involvement,arrhythmias,fibrosisoftheconductionsystem,pacemakerandintracar-diac defibrillator implantation, sudden death and autonomic dysfunc-tion [2,3].Amongtheabnormalities in SSc,QTc intervalprolongation hasbeenreportedandassociatedwithanti-RNApolymeraseIIIantibodies,longerdisease duration, and greater disease severity [4].Accordingly,theaimofthestudyistoassessQTcprolongationinSScand evaluate correlations with clinical variables and complications ofthe disease.The protocol is in accordance with the Declaration of Helsinki andwas approved by the Ethics Committee at our Institution. Twenty Cau-casian subjects fulfilling the American Rheumatism Association (ARA)criteria for classification and diagnosis of SSc [5] and twenty healthysubjectswereexaminedbeforeinclusioninthestudy.All examined pa-tientsunderwentclinicalevaluation,ambulatory24-hourECGmonitor-ing, transthoracic echocardiogram.Scleroderma patients with coronary artery disease, congestiveheartfailure, left ventricular dysfunction, significant valvular abnormalitiesand arrhythmias were not included in the study.Patients with pulmonary function abnormalities were not includedeither. Patients with diabetes mellitus, renal failure, hepatic or thyroiddysfunction, and anemia were excluded.Patients were not takingβ-blockers, antiarrhythmic drugs,ACE-inhibitors or angiotensin receptor antagonists. QTc interval,assessed by 24-hour Holter ECG recording, was defined as prolongedwhen N440 ms [6].Nailfold videocapillaroscopy (NVC) was performed by an opticalprobe, equipped with magnification 200× contact lens and connectedto image analysis software (Pinnacle Studio Version 8). The identifiedpatterns were classified as early, active or late [7]. Skin thickening wasassessed by a modified Rodnan total skin score (mRSS) [8]. In all pa-tientswemeasuredtheDiseaseActivityIndex(DAI)andDiseaseSever-ity Scale (DSS) [9].Thedatawereexpressedasmedianandrange.Multivariateanalysiswas applied for the estimation of relationship of QTc with disease vari-ables. The Mann–Whitney U-test or Kruskal–Wallis were used to testdifferences between two individual study groups. Spearmans rankorder correlation coefficient (r) was used to test for an association be-tweennumericalvariables.p-Valuesb0.05wereconsideredsignificant.Commercial software (SPSS version 20.0) was used for statisticalanalysis.Twentysclerodermapatientswereenrolledinthecurrentstudy.Theepidemiological and clinical features of SSc are shown in Table 1.ThemedianvalueofQTcissignificantly(pb0.0001)increasedinSScpatients than healthy controls [447 (414–566) vs 386 (342–447)].The medianvalueof QTc is significantly (p b 0.01) different in threecapillaroscopicgroups:early425(421 –454),active437(416–467),late471 (445–566).ThemedianvalueofQTcissignificantly(pb 0.05)augmentedin SScpatients with digital ulcers than in SSc patients without digital ulcers[459(422–566)vs436(416–454)].Apositivecorrelation (p b0.05)ex-ists between QTc and mRSS (r = 0.53).NocorrelationswerefoundbetweenQTcanddiseasesubset,diseaseduration, Disease Activity Index, and Disease Severity Scale.Amongthe causes of suddencardiacdeath in SScpatients,ventricu-lar late potentials, autonomic dysfunction, pro-arrhythmogenic drugsand increased QT dispersion were found.

Correlation between intrarenal arterial stiffness and exercise tolerance in systemic sclerosis patients without renal and cardiopulmonary impairment: The role of the microvascular damage

Correlation between intrarenal arterial stiffness and exercise tolerance in systemic sclerosis patients without renal and cardiopulmonary impairment: The role of the microvascular damage Antonietta Gigante ⁎, Antonella Romaniello , Damiano Magri , Matteo Bonini , Biagio Barbano , Liborio Sardo , Silvia Quarta , Maria Anna Digiulio , Marcello Di Paolo , Rosario Cianci , Paolo Palange , Antonio Amoroso , Edoardo Rosato a

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.

Safety and infectious prophylaxis of intravenous immunoglobulin in elderly patients with membranous nephropathy.

A variety of infections has been recognized as an important cause of morbidity and mortality in patients with nephrotic syndrome, and membranous nephropathy is a common cause of this in the elderly. The reasons for infection risk are due to oedema complications, urinary loss of factor B and D of the alternative complement pathway, cellular immunity, granulocyte chemotaxis, hypogammaglobulinemia with serum IgG levels below 600 mg/dL, and secondary effects of immunosuppressive therapy. Many different prophylactic interventions have been used for reducing the risks of infection in these patients but recommendations for routine use are still lacking. We report two membranous nephropathy cases in the elderly in which Intravenous immunoglobulin were useful in long-term infectious prophylaxis, showing safety in renal function. During immunosuppressant therapy in membranous nephropathy, intravenous immunoglobulin without sucrose are a safe therapeutic option as prophylaxis in those patients with nephrotic syndrome and IgG levels below 600 mg/dL. The long-term goal of infection prevention in these patients is to reduce mortality, prolong survival and improve quality of life.

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.