[Does clinical methodology yet exist?] / Metodologia in clinica: esiste ancora?

Up to 1968, clinical methodology was considered a central step in construction of Medical procedure. Later, after specialization or high specialization introduction, it totally disappeared. The results is the absence of any epistemological knowledge in the construction of diagnosis, based on two main theory: inductivism and hypothetico-deductivism. Both start from the point that diagnostic theory can be developed in close touch with experiment and observation. The inductive theory builds up the diagnosis on the multiple observations, while the deductive theory formulates the diagnosis from the bright idea which inspires the doctor who then has to check his theory by observation. The difference between two approaches to diagnosis is based on the tabula rasa of inductive physician and tabula plena of deductive physician. Without a methodology knowledge, the new doctors are lacking of proper correct approach to right diagnosis and therapy and rarely use academic tools to deepen it in clinical work. We consider many epistemology clinical aspects related to science and medical practice. In addition, we point out the attention to some cases on the basis of new inductive and deductive theories, in order to have respect for patients and doctors dignity.

[Cardionephrology: past, present and future]. / Cardionefrologia: passato, presente e futuro.

In 1987, the first Kidney-Heart meeting was held in Assisi, Italy and in 1991 the term Cardionephrology was coined in medical practice. Since then, nephrologists and cardiologists realized the utility of a tight cooperation among them and organized an agenda of scientific meetings which take place every two years within European countries. The cooperation was strengthened by daily observation which shows renal replacement therapy had solved many problems but imposed or added new disorders to cardiovascular system. Soon, the nephrologists learned that hemodialyisis techniques had not only blood detoxification effect but also cardiovascular consequences. Therefore, the nephrologists started to adopt cardiological tools and apply them to renal patients. The cardiologists realized that in some aspects kidney patients are different from non-renal cardiological patients and have to be treated differently. In Assisi Cardionephrology meetings a clear message was launched: the necessity to bring nephrologists and cardiologists together with the potential benefit of learning from others experiences and transferring the outcome for the benefit of our patients. As result, many foundations and journals have been emerged on this topic. Is there a future for Cardionephrolgy? The answer is yes, with a unique limitation: to continue the spirit of Assisi, following the culture of cooperation and relying on RCTs hypothesis.

[Assessment of right ventricular function in patients with chronic kidney disease stage IV NKF]. / Valutazione della funzione ventricolare destra in pazienti affetti da malattia renale cronica in stadio I-V NKF.

Cardiovascular diseases are accountable for almost 50% of over-all mortality rates in chronic kidney disease (CKD) patients, especially in those who undergo hemo-dialysis or peritoneal dialysis.Hemodialysis patients present higher rates of pulmonary hypertension (PH), an independent risk factor for cardiovascular mortality among this patient population, due in part to the presence and hemodynamic effects of vascular access (both artero-venous fistula and central venous catheter). Echocardiographic TAPSE (tricuspid annular plane systolic excursion) index represents a helpful tool for investigation of right ventricular function together with PAPs (systolic pulmonary artery pressure) evaluation.The following study protocol, introduced by the Cardionephrology Study Group of the Italian Society of Nephrology, aims to evaluate the incidence of right ventricular dysfunction and PH in CKD patients. This is a multicentric, case- control study which includes two arms, each comprising 200 patients, and which will last 24-36 months.Glomerular filtration rates (GFR) are calculated using the eGFR EPI equation, while echocardiographic evaluation includes atrial and ventricular dimension and area, left ventricular systolic function (ejection fraction), diastolic function, TAPSE index measurement and PAPs evaluation.

[The nephrologist and the role of ultrasound imaging in the diagnosis of cardiorenal syndrome]. / Il nefrologo e il ruolo dell'imaging ultrasonografico nella diagnosi di sindrome cardio-renale.

The term cardiorenal syndrome (CRS) refers to multiple possible clinicopathological correlations between heart and kidney failure. The most recent classification recognizes five types of CRS: types I and II originate from heart failure (acute and chronic, respectively), type III and IV from kidney failure (again acute and chronic), while type V originates from a range of systemic diseases. Echocardiography and renal ultrasound are important means to arrive at a correct diagnosis. Basic echocardiography (defined by some as "echocardioscopy") allows the assessment of the left and right ventricles (diastolic and systolic function), atrial size, pulmonary circulation markers such as systolic pulmonary arterial pressure (PAPs) and tricuspid annular plane excursion (TAPSE), pericardial effusions, valve dysfunctions, and volume repletion. Renal ultrasound is of help in distinguishing between chronic and acute renal failure (kidney volume, parenchymal thickness, echogenicity) and excluding obstructive kidney disease.

Ultrasonography: Ariadne's Thread in the Diagnosis of the Cardiorenal Syndrome.

The term cardiorenal syndrome (CRS) describes a broad spectrum of clinical conditions with four combinations of acute and chronic heart and kidney failure. Based on the pathophysiological primum movens, the actual classification recognizes five CRS types: in type I and II CRS, the initiating event is heart failure (acute or chronic), while it is kidney failure in type III and IV CRS; type V is linked to systemic diseases. Ultrasound techniques (echocardiography and ultrasonography of the kidney, inferior vena cava and chest) can be extremely helpful in establishing a prompt diagnosis and a correct CRS classification. Basic echocardiography allows evaluation of ventricular diastolic and systolic functions, investigates pulmonary congestion and pericardial effusion, and describes volume overload. On the other hand, renal ultrasound helps clinicians to distinguish between acute and chronic renal failure, excludes urinary tract dilation or pathological bladder repletion, and provides crucial information regarding kidney volume or echogenicity. Applying basic knowledge of echocardiography and renal ultrasound, nephrologists may be in a better position for patient treatment and management, bearing in mind that doctors can properly use a stethoscope although not being a cardiologist.

[Uric acid and cardiorenal risk: marker or cause?]. / Acido urico e rischio cardiorenale: marker o concausa?

An association between high levels of serum uric acid and cardiovascular as well as renal disease has been proposed for many decades. However, only recently compelling basic science data, small clinical trials, and epidemiological studies have provided support to the idea of a true causal effect. In this noncomprehensive review, we present recently published data that evaluate the association between hyperuricemia and selected cardiovascular and renal diseases, with a final conclusion about the possibility of this association being causal.

Main results of the ouabain and adducin for Specific Intervention on Sodium in Hypertension Trial (OASIS-HT): a randomized placebo-controlled phase-2 dose-finding study of rostafuroxin.

BACKGROUND: The Ouabain and Adducin for Specific Intervention on Sodium in Hypertension (OASIS-HT) Trial was a phase-2 dose-finding study of rostafuroxin, a digitoxygenin derivative, which selectively antagonizes the effects of endogenous ouabain (EO) on Na+,K+-ATPase and mutated adducin. Rostafuroxin lowered blood pressure (BP) in some animal models and in humans. METHODS: OASIS-HT consisted of 5 concurrently running double-blind cross-over studies. After 4 weeks without treatment, 435 patients with uncomplicated systolic hypertension (140-169 mm Hg) were randomized to rostafuroxin (0.05, 0.15, 0.5, 1.5 or 5.0 mg/d) or matching placebo, each treatment period lasting 5 weeks. The primary endpoint was the reduction in systolic office BP. Among the secondary endpoints were diastolic office BP, 24-h ambulatory BP, plasma EO concentration and renin activity, 24-h urinary sodium and aldosterone excretion, and safety. ANOVA considered treatment sequence (fixed effect), subjects nested within sequence (random), period (fixed), and treatment (fixed). RESULTS: Among 410 analyzable patients (40.5% women; mean age, 48.4 years), the differences in the primary endpoint (rostafuroxin minus placebo) ranged from -0.18 mm Hg (P = 0.90) on 0.15 mg/d rostafuroxin to 2.72 mm Hg (P = 0.04) on 0.05 mg/d. In the 5 dosage arms combined, the treatment effects averaged 1.30 mm Hg (P = 0.03) for systolic office BP; 0.70 mm Hg (P = 0.08) for diastolic office BP; 0.36 mm Hg (P = 0.49) for 24-h systolic BP; and 0.05 mm Hg (P = 0.88) for 24-h diastolic BP. In the 2 treatment groups combined, systolic (-1.36 mm Hg) and diastolic (-0.97 mm Hg) office BPs decreased from week 5 to 10 (P for period effect ≤ 0.028), but carry-over effects were not significant (P ≥ 0.11). All other endpoints were not different on rostafuroxin and placebo. Minor side-effects occurred with similarly low frequency on rostafuroxin and placebo. CONCLUSIONS: In 5 concurrently running double-blind cross-over studies rostafuroxin did not reduce BP at any dose. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT00415038.

Association of uric acid with change in kidney function in healthy normotensive individuals.

BACKGROUND: Despite recent evidence, the role of uric acid as a causal factor in the pathogenesis and progression of kidney disease remains controversial, partly because of the inclusion in epidemiologic studies of patients with hypertension, diabetes, and/or proteinuria. STUDY DESIGN: Prospective observational cohort. SETTING & PARTICIPANTS: 900 healthy normotensive adult blood donors (153 women, 747 men) evaluated at baseline and after 5 years. PREDICTOR: Serum uric acid level. OUTCOMES: Decrease in estimated glomerular filtration rate (eGFR) >10 mL/min/1.73 m(2), computed using the Modification of Diet in Renal Disease (MDRD) Study equation, with secondary analyses examining similar decreases using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Cockcroft-Gault equations. RESULTS: During a median follow-up of 59 months, eGFR decreased from 97 +/- 16 to 88 +/- 14 mL/min/1.73 m(2). Higher serum uric acid levels were associated with a greater likelihood of eGFR decrease in both women and men (HR, 1.13 [95% CI, 1.04-1.39] per each 1-mg/dL increase in uric acid level); in multivariable analyses adjusting for age, sex, body mass index, blood glucose level, total cholesterol level, mean blood pressure, urine albumin-creatinine ratio, and serum triglyceride level, the association remained highly significant (HR, 1.28 [95% CI, 1.12-1.48]). Results were similar using different estimating equations and when the association was examined in sex-specific subgroups. LIMITATIONS: Analyses were based on a single baseline uric acid measurement. Women are underrepresented. CONCLUSIONS: In healthy normotensive individuals, serum uric acid level is an independent risk factor for decreased kidney function.

Microalbuminuria and uric acid in healthy subjects.

BACKGROUND: Microalbuminuria has been linked to cardiovascular (CV) risk in patients with diabetes or hypertension, and in an unselected general population; serum uric acid (UA) is emerging as a novel risk factor for CV disease. The aim of our study was to evaluate the prevalence of excess microalbuminuria and its relation to established CV risk factors and serum UA in healthy subjects. METHODS: We screened 900 healthy blood donors (age range, 20-65 years; 747 men, 153 women), and measured total, HDL and LDL cholesterol, blood glucose, serum and urinary creatinine, serum UA, blood pressure (BP) and microalbuminuria (urinary albumin/creatinine ratio, ACR). The Framingham risk score was also calculated. RESULTS: After excluding 52 participants, we found that in 848 participants (702 men, 146 women) the overall prevalence of excess ACR, using a 30 mg/g creatinine cutoff, was 9.3% (9.7% of men, 7.5% of women, p=0.16); adopting a gender-dependent cutoff, we found that the overall prevalence was 13.6% (15.1% of men, 6.2% of women, p<0.01). ACR was highly correlated to diastolic (r=0.88, p<0.001) and systolic (r=0.74, p<0.001) BP, and also--though not as strongly--to serum UA (r=0.38, p<0.001). In a stepwise multiple regression model, systolic and diastolic BP, total cholesterol, serum creatinine and UA were segregated as independent predictors of microalbuminuria (model R=0.91, R square=0.83). Correlation of serum UA to ACR remained significant, albeit attenuated (r=0.09, p=0.02), after adjustment for serum creatinine, total cholesterol, systolic and diastolic BP. CONCLUSIONS: The results of our study show ACR to be abnormal in a significant proportion of seemingly healthy subjects, and serum UA to be an independent predictor of microalbuminuria.

Inflammation, infection and cardiovascular events in chronic hemodialysis patients: a prospective study.

BACKGROUND: Cardiovascular (CV) disease is the leading cause of morbidity and mortality in chronic hemodialysis (HD) patients. Inflammation is a potent risk factor for CV disease in the general population. Recent evidence suggests infection, particularly with agents such as Chlamydia pneumoniae (C.pneumoniae) and Helicobacter pylori (H.pylori), as a source of sustained inflammation. Our study tested the hypothesis that C-reactive protein (CRP) and positive serology for antibodies to C.pneumoniae and H.pylori can be associated with the occurrence of new CV events in chronic HD patients. METHODS: We evaluated 76 chronic HD patients (33 women and 43 men, aged 60.5+/-17.3 years) by measuring baseline CRP levels as well as the titres of antibodies (IgG and IgA) to C.pneumoniae and(IgG) to H.pylori. In addition, risk factors such as hypertension, smoking, diabetes, cholesterol levels and albumin were assessed at baseline. The incidence of new CV events (myocardial infarction and ischemic stroke) was recorded during a 36-month follow-up period. The effect of prognostic factors was evaluated by logistic regression analysis. RESULTS: The incidence of CV events was significantly higher in patients seropositive for C.pneumoniae antibodies than in those seronegative (16.1 vs. 4.3 events/100 patient-years, p=0.017, risk ratio 3.76), whereas it did not differ for H.pylori (12.2 vs. 11.7 events/100 patient-years,p=0.91, risk ratio 1.04). Logistic regression analysis showed C.pneumoniae seropositivity (odds ratio 10.11, p=0.04) and CRP levels (odds ratio 1.78, p=0.03) to be independent predictors of the occurrence of CV events. CONCLUSIONS: CRP levels and C.pneumoniae antibodies, but not H.pylori antibodies, were predictors of CV morbidity in the chronic HD patients studied.

Theories and controversies on urine formation.

The theories of urine formation developed in the wake of progressing scientific knowledge in renal anatomy and physiology. From the philosophical theories which for a long time swung between vitalism and mechanism, the "scientific revolution" gave a great impulse to morpho/functional unit of kidney. Bowman's secretory hypothesis, as an expression of the vitalistic based theory, describes for the first time many features of the nephron and its blood supply. New insight into the inevitable errors of Bowman led Ludwig to develop the filtration-reabsorption theory, which based its scientific approach on the emerging physics and chemistry theories. The Heidenhain's secretory hypothesis which does not admit the physical filtration in Ludwig's sense, nor the hydrostatic pressure of the blood, even though incomplete and in some part without unequivocal experimental evidence, adds a fragment to the right theory of the urine formation and heralds the modern approach to the renal function of the 20th century.

Ippolito Albertini and Michael Albertus: disparate old and innovative theories on dropsy and edema.

The concept of edema and dropsy as a part of heart and renal failure developed in the 17th and 18th centuries with the observations of Albertini, who realized that two clinical entities were derived from the blood rather than the tissues. Albertus, who lived in the same period, was the last physician to interpret fluid accumulation according to the old, scholastic and dogmatic procedures of medicine. The fundamental concepts of Albertus held little in addition to the classification and categories of the physicians of the Middle Ages. Bloody congestions were distinguished from stagnation: the former have the purpose of reducing superfluites of blood and occurred in plethoric patients. Plethora in turn is caused by the ancient villain, inculpated since Hippocrates and Galen: suppressed hemorrhoids, suppressed menstrual evacuation and cutaneous eruption driven inward. Because of its suppression, transfer of blood occurs toward the chest, which impedes thoracic expansion and contraction, then asthma and dyspnea occur. On the contrary, Albertini with his clinical and autoptic observations and pronouncements filled in the anatomical and clinical picture of fluid accumulation and created the rudiments of diagnostic criteria. Edema, dropsy, asthma, dyspnea were, according to Albertini, the signs and symptoms of heart and renal failure. Albertini was the first to point out that dyspnea is apt to arise with special rapidity when a lesion occurs in the left atrial chamber and ventricle and by implication the mitral valve. In modern physiopathological terms, he discovered the picture of pulmonary edema. To this important discovery, he added a number of extremely important comments: changes in the respiratory organs are secondary to changes in the cardiovascular system; edema that is accompanied by dyspnea also affects the viscera, most especially the lungs, and finally dropsy of the lungs must be differentiated anatomically and clinically from dropsy of the chest (hydrothorax). In other words, he depicted the anatomical and clinical picture of congestive heart failure in modern terms.