Sodium retention in preascitic stage of cirrhosis.

Renal Na+ handling abnormalities have been shown in preascitic cirrhosis. To investigate the underlying pathophysiology, the effects of different sodium intakes on Na(+) balance and renal hemodynamics were assessed at 100 mEq Na+/day (low-sodium diet [LSD]) and after 6 days of 250 mEq Na+/day (high-sodium diet [HSD]). Eight asymptomatic patients with cirrhosis (Pugh-Child A class) (PAC) and 10 healthy controls (CON) were studied. At HSD, although CON readjusted Na+ excretion within the fourth day, PAC did not reach the new balance and developed a final greater Na+ retention (+437 mEq in PAC v +228 mEq in CON, P<.001). In PAC, fractional Na+ excretion (FENa) was significantly lower than in CON at LSD (P<.05), and, after HSD, increased in both groups (P<.05). In PAC, renal vascular resistances (RVR) at LSD resulted lower than in CON (P<.05) and failed to decrease after HSD. As a consequence, after HSD, glomerular filtration rate and renal plasma flow failed to increase in PAC. PRA and plasma aldosterone were significantly lower in PAC, than in CON at LSD (P<.05), and decreased in both groups after HSD (P<.05). Proximal Na+ reabsorption (RProx) [as indicated by fractional free water clearance measured in a state of maximal water diuresis] at LSD was lower in PAC than in CON (P<.05) and decreased in both groups after HSD (P<.05). In summary, early stages of cirrhosis are characterized by: (1) a reduction of RVR, probably associated with splanchnic vasodilation; (2) a Na+ retention already at LSD, as indicated by the lower FENa observed in PAC, that produces extracellular volume (ECV) expansion, with a consequent RProx and renin-angiotensin-aldosterone axis (RAS) suppression; (3) a greater Na+ retention after HSD, associated with an abnormal adaptation of renal hemodynamic, a greater ECV expansion and a consequent Rprox and RAS suppression. These data show the presence of early renal hemodynamic dysfunction in PAC. Our findings also show in this phase of the disease a preserved adaptation of RProx and RAS, thus suggesting that the observed tubular Na+ reabsorption derangement is probably related to abnormal ANP behavior.

Early impairment of renal hemodynamic reserve in patients with asymptomatic heart failure is restored by angiotensin II antagonism.

BACKGROUND: The early/asymptomatic stages of heart failure (HF) are characterized by sodium retention secondary to derangement of sodium reabsorption at the proximal nephron level. Because this phenomenon is reversed by ACE inhibition, abnormalities of renal sodium handling may depend on intrarenal changes of angiotensin II (AII)/nitric oxide (NO) levels. Renal hemodynamic reserve (ie, the glomerular vasodilatory response to amino acid infusion) has been proposed as a reliable test to assess in vivo AII/NO balance. METHODS AND RESULTS: In this study, the effects of 6 weeks of treatment with 5 mg/d of enalapril or with 50 mg/d of losartan on systemic hemodynamics and renal function were assessed, at baseline and after amino acid infusion (AA), in patients with mild HF (NYHA class I) and in healthy volunteers. Untreated HF patients showed a basal renal function comparable to that of healthy subjects. After AA, glomerular filtration rate and renal plasma flow significantly increased in healthy subjects (+29.0% and +30.4%, respectively), whereas no vasodilatory response was observed in HF. Although they did not affect basal renal hemodynamics, both enalapril and losartan restored a normal response to AA in HF patients. Blood pressure and heart rate were comparable in HF subjects and healthy subjects at baseline and were not modified by either treatment. Left ventricular ejection fraction was depressed in HF but did not change after either drug. Urinary excretions of cGMP and nitrate (indexes of NO activity in the kidney), comparable in healthy subjects and in HF patients, were unchanged by either enalapril or losartan and did not correlate with renal reserve. CONCLUSIONS: (1) Renal functional reserve is absent in patients with early/asymptomatic HF and normal renal function and (2) both enalapril and losartan restore a normal vasodilatory response to AA in these patients without affecting basal systemic and renal hemodynamics. These data suggest a major role of AII in the development of early abnormalities in patients with HF.

Urinary excretion of free and acetylated polyamines in hepatocellular carcinoma.

Polyamines (putrescine, spermidine and spermine) are essential for the proliferation of normal and neoplastic cells, and have been repeatedly recommended as tumor markers, with contrasting and elusive results. In the present study the urinary excretion of free and acetylated polyamines was measured in patients with hepatocellular carcinoma (HCC), cirrhotics and control subjects. Separation and quantification of dansyl-derivatives of free, acetylated and total polyamines was performed by reverse-phase high-performance liquid chromatography. The results show that the urinary excretion of total, free, and acetylated polyamines is significantly higher in HCC patients than in cirrhotics and controls (p < 0.001). The N1/N8 acetyl-spermidine molar ratio was found to be higher in HCC patients than in cirrhotics and controls (p < 0.001). No correlation was found between urinary excretion of polyamines and serum alpha-fetoprotein, tumor size and severity of liver cirrhosis. The results show that increased urinary excretion of free and acetylated polyamines, as well as an altered N1/N8-acetyl-spermidine molar ratio, is a sensible but not specific feature of HCC patients; polyamines may play a role in human carcinogenesis, but their determination does not seem reliable for the early detection of liver cancer.

The impact of early normalization of haematocrit by erythropoietin on renal damage in the remnant kidney model.

BACKGROUND: Correction of anaemia in moderate to advanced renal failure is still a matter of debate because of postulated detrimental effects of erythropoietin on the progression of renal damage. METHODS: The renal effects of early normalization of haematocrit (Htc) by erythropoietin (rHuEpo) were investigated from the time of 5/6 nephrectomy up to 8 weeks post-intervention in three groups of remnant kidney model rats: untreated controls (CON), rats receiving 100 UI/kg body-wt of rHuEpo i.p. twice a week (EPO), and rats receiving rHuEpo in which periodic phlebotomies maintained Htc similar to the value of the control group (PHL). The latter group was included to evaluate the direct effects of rHuEpo on renal damage, i.e. independent from Htc correction. RESULTS: Two weeks after renal ablation (basal), Htc decreased in CON and PHL rats (from 49.3+/-1.4% to 43.2+/- 1.1, P < 0.05 and from 49.6+/-1.1 to 43.3+/-1.5%, P<0.05 respectively), while it remained consistently normal in EPO rats (48.9+/-1.2% to 48.9+/-1.50/%, P<0.05 vs other groups). Thereafter Htc did not change throughout the remaining period in all groups. At the end of the study, with respect to basal, resting blood pressure increased significantly by the same extent in CON (+ 13+/-2%) and EPO rats (+ 15+/-5%), while it remained constant in PHL rats. Notably, creatinine clearance significantly decreased in CON (-53+/-8% 8 vs basal) and EPO (-38+/-8% vs basal), while it did not change in PHL rats. Likewise the degree of proteinuria as well as renal morphologic alterations and glomerular hypertrophy/sclerosis was similar in CON and EPO rats, and was significantly more severe than in the phlebotomized group. The only difference detected between CON and EPO group was the greater mesangial hypercellularity in rHuEpo-treated rats. CONCLUSION: In uraemic rats, chronic treatment with rHuEpo aimed at normalization of Htc beginning the early stage of renal failure does not inevitably account for a rise in systemic blood pressure. In addition, neither erythropoietin per se nor the correction of haematocrit accelerates the progression of renal damage when blood pressure remains constant.

Role of tissue renin in the regulation of aldosterone biosynthesis in the adrenal cortex of nephrectomized rats.

The aim of the study was to investigate whether the adrenal renin-angiotensin system plays an independent role in the regulation of mineralocorticoid biosynthesis in the adrenal gland and to explore the mechanisms of this action. Twelve-week-old male Sprague-Dawley rats were studied: 22 rats were maintained on a regular diet; 27 and 22 rats received a low salt diet with and without treatment, respectively, with the angiotensin II (Ang II) AT1-subtype receptor antagonist losartan (10 mg/kg per day). A fraction of each group of rats underwent bilateral nephrectomy (n = 12, 15, and 10, respectively) and was killed 48 hours later. In an additional group of 24 (12 intact and 12 nephrectomized) rats, the effects of the Ang II AT2-subtype receptor antagonist PD123319 were investigated. In intact rats, plasma renin activity (PRA) and adrenal renin activity and expression were progressively raised by salt restriction and losartan, whereas aldosterone synthase mRNA and plasma aldosterone (PA) levels were increased by salt restriction and reduced by losartan. Forty-eight hours after nephrectomy, PRA fell to undetectable levels; in contrast, adrenal renin expression, assessed by semiquantitative reverse-transcriptase polymerase chain reaction (using GAPDH as a standard for gene expression), showed an 18-fold increase and was further increased after salt restriction and losartan (all P < .05). Also, adrenal renin activity was raised after nephrectomy and further increased after salt restriction (P < .05) and losartan. Cytochrome P450 aldosterone synthase expression in the adrenal cortex was stimulated by nephrectomy alone and by nephrectomy combined with low salt intake (P < .05), with consequent increases in PA concentrations. In losartan-treated salt-restricted nephrectomized rats, cytochrome P450 aldosterone synthase expression (P < .05 versus nephrectomy alone and nephrectomy plus salt restriction) and PA concentrations were diminished (P < .05) in spite of the observed increases of adrenal renin expression. The AT2-receptor antagonism did not significantly affect PRA, adrenal renin, and aldosterone biosynthesis and production in either intact or nephrectomized salt-restricted rats. These results demonstrate that the adrenal renin-angiotensin system plays an independent role in the regulation of mineralocorticoid biosynthesis in vivo. This action is mediated primarily via the Ang II AT1-subtype receptors.

Intrarenal determinants of sodium retention in mild heart failure: effects of angiotensin-converting enzyme inhibition.

The onset and the mechanisms leading to Na+ retention in incipient congestive heart failure (CHF) have not been systematically investigated. To investigate renal Na+ handling in the early or mild stages of CHF, Na+ balance and renal clearances were assessed in 10 asymptomatic patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (HF) off treatment (left ventricular ejection fraction, 29.7+/-2%) and in 10 matched normal subjects during a diet containing 100 mmol/d of NaCl and after 8 days of high salt intake (250 mmol/d). Six patients were studied again after 6 weeks of treatment with enalapril (5 mg/d P.O.). At the end of the high salt diet, in patients with mild HF the cumulative Na+ balance exceeded by 110 mmol that of normal subjects (F=3.86, P<.001). During high salt intake, renal plasma flow and glomerular filtration rate were similarly increased in both normal subjects and mild HF patients. In spite of comparable increases of filtered Na+ in the two groups, fractional excretion of Na+, fractional clearance of free water, and fractional excretion of K+ (indexes of distal delivery of Na+) increased in normal subjects and were reduced in patients with mild HF. During enalapril treatment, in the mild HF patients the cumulative Na+ balance was restored to normal; furthermore, enalapril significantly attenuated the abnormalities in the distal delivery of Na+. Our results indicate that a defective adaptation of Na+ reabsorption in the proximal nephron is associated with Na+ retention in response to increased salt intake in the early or mild stages of HF. These abnormalities of renal Na+ handling are largely reversed by enalapril.

Serial morphometric analysis of sclerotic lesions in primary "focal" segmental glomerulosclerosis.

The possibility of missing the diagnosis of focal segmental glomerulosclerosis (FSGS) has been primarily attributed to the focal distribution of the sclerotic lesions, but this assumption has not been verified by any serial morphometric analysis of renal biopsy specimens. The aim of this study is to assess the size and the distribution of sclerotic lesions in primary FSGS and to establish the minimum number of glomeruli and sections necessary for the diagnosis. Fourteen biopsies from adult nephrotic patients with primary FSGS were carefully selected from a group of 41 biopsies, to minimize the possibility of finding and misinterpreting nonspecific glomerular scars, and were serially cut to obtain 1485 consecutive 2 microns-thick sections that, after PAS staining, showed 182 glomeruli. Fifty-seven glomeruli were "complete", i.e., they emerged after the first section and disappeared before the last section. The percentage of glomeruli with sclerotic lesions was 31.5% in the starting section, 71.8% after the observation of all serial sections, and 81.7% when only the complete glomeruli were considered. The morphometric analysis on complete glomeruli revealed that the volume of the sclerotic lesions averaged just 12.5% +/- 2.2 SE of the entire glomerular volume, and the statistical analysis revealed that the minimum number of glomeruli needed in the starting section to exclude sclerotic lesions is eight (P < 0.01) or nine (P < 0.001). If fewer glomeruli are seen, it is necessary to cut 2 microns-thick serial sections, but to examine just one of every 11 (P < 0.001), the number of sections to examine being proportional to the number of glomeruli found. In conclusion, this study shows that the distribution of sclerotic lesions in primary FSGS is not focal, but diffuse; however, because of the small size of the sclerotic lesions, the probability of missing the diagnosis is statistically relevant when fewer than eight glomeruli are found in the starting section, unless a serial morphological analysis, even on a reduced number of sections, is made.

Serum neopterin levels in patients with hepatocellular carcinoma.

Increased concentrations of neopterin have been found in conditions causing a stimulation of cellular immunity, including various malignancies. In liver diseases, serum or urinary neopterin levels have been studied in acute viral hepatitis, chronic hepatitis, fatty liver and liver cirrhosis. In the present study neopterin serum levels have been measured in 16 patients with hepatocellular carcinoma (HCC), in 32 patients with liver cirrhosis, and in 28 healthy subjects as controls. Mean values of serum neopterin were significantly increased (p < 0.01) in patients with HCC (15.89 +/- 6.34 nmol/l) when compared with those of normal subjects (4.74 +/- 2.13 nmol/l), but no difference was observed between patients with HCC (associated or not with liver cirrhosis) and patients with liver cirrhosis. Neopterin concentrations are not affected by liver cirrhosis aetiology, nor by its clinical severity, and are not correlated to the values of serum alpha-fetoprotein, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl-transferase, and gamma-globulin. The results show that there is a consistent overlap of values in patients with HCC and liver cirrhosis; macrophage activation seems to be a feature of chronic liver diseases, irrespective of HCC development.

POEMS syndrome: an Italian case with diagnostic and therapeutic implications.

A young Italian patient with a multisystem disorder and a solitary osteosclerotic bone lesion is described. His clinicopathological situation involved sensory-motor polyneuropathy, organomegaly, endocrine dysfunction, skin alterations, edema of the lower limbs and generalized lymphadenopathy. These features were consistent with the diagnosis of POEMS syndrome, reported primarily in Japanese patients. M components were not found in this patient's serum or urine. Bone marrow biopsy showed only a slight plasma cell infiltrate; histological study of the sural nerve evidenced a mixture of both axonal degeneration and segmental demyelinization. Lymph node biopsy revealed peculiar pathological changes resembling those of type II Castleman-like disease. A wide bone defect with osteosclerotic margins and trabeculation was evidenced in the right ilium. The relationship of these findings to plasma cell dyscrasias is discussed. After prednisone and local radiotherapy failed, the patient was treated with human recombinant interferon for 18 months. After three months of therapy he has experienced remarkable improvement of his neurological symptoms and almost complete recovery of organomegaly and lymphadenopathy. These improvements have continued to the present.

beta-Hexosaminidase activity in the acute phase of CCl4 poisoning in the rat.

beta-Hexosaminidase (Hex) activity has been shown to be increased in the sera of patients with chronic liver diseases as well as in rats with CCl4-induced liver cirrhosis. In this study, serum and liver Hex activity was determined in rats during the acute phase of CCl4 poisoning, a widely used animal model of acute necrotic liver damage. The results showed a statistically significant decrease of Hex activity in the sera of rats 36 h after CCl4 poisoning (5.84 +/- 2.90 U/l), as compared to controls (11.58 +/- 1.35 U/l; p less than 0.001). No significant change was observed in liver tissue of CCl4-treated animals and controls. A significant correlation between the decrease in Hex and the increase in serum aspartate aminotransferase in serum was found. The results are consistent with the hypothesis that this lysosomal enzyme could be released by non-parenchymal liver cells, such as activated macrophages; its increased activity could be the expression of macrophage activation, as demonstrated in patients with chronic liver diseases.

Serum neopterin levels in liver cirrhosis.

Neopterin is a pyrazino-pyrimidine compound which is biosynthesized by macrophages. Increased concentrations of neopterin have been reported in conditions causing a stimulation of cellular immunity, such as viral and other infections, graft versus host disease, autoimmune disease and different malignancies. Recently, urinary neopterin levels have been found increased in patients with acute viral hepatitis and NANB chronic hepatitis. In the present study, neopterin serum levels have been measured in 23 cirrhotic patients (6 HBV related, and 17 cryptogenetic cirrhosis, 7 of them occurring in alcoholic subjects) and in 24 normal subjects. Mean values of serum neopterin were significantly increased in cirrhotics (3.92 +/- 3.28 ng/ml versus 1.24 +/- 0.51 ng/ml in controls, p less than 0.01). Serum neopterin values were not found to be significantly different in cirrhotics assessed in three different clinical classes according to Child's classification and in cirrhotics with and without serological findings of active disease. In fact, in cirrhotic patients, serum neopterin levels did not correlate with the values of serum AST, ALT, ALP, GGT and gamma-globulin. These data show that increased levels of serum neopterin occur in cirrhotic patients, but there is no relation between serum neopterin values and the activity or the clinical severity of the disease. The results are consistent with the hypothesis that activated macrophages are involved in all stages of liver cirrhosis irrespective of its aetiology.

Combination of tissue polypeptide antigen (TPA) and carcino embryonic antigen (CEA) in different types of cancer.

Tissue polypeptide antigen (TPA) and carcino embryonic antigen (CEA) were measured in 55 patients with cancer in different locations (21 lung cancer, 133 breast cancer, 9 stomach cancer, 5 colorectal cancer, 7 cancer of unknown origin). TPA gives elevated values in all types of cancer. The statistical analysis shows that TPA is about equally sensitive for all cancer types, while CEA has a particularly high sensitivity for colorectal carcinoma. The TPA values in the group of cancer patients is significantly different from those in a group of healthy controls. TPA gives higher sensitivity than CEA in all tumour locations. By the use of combined determination of TPA and CEA the sensitivity can be further increased, to 64% for the whole patient population and 89% for the gastric tumour patients, even when the cut-off values are chosen so high that no false positives are obtained in either reference group (150 Ul-1 for TPA, 10 ng ml-1 for CEA). A limited correlation exists between the markers in tumour patients.

[Diagnostic and therapeutic importance of breast pain]. / L'importanza diagnostica e terapeutica del dolore mammario.

In matters of mammary pathology, the attention of students has always been attracted by the study of tumours, while the varied field of mastalgia has been somewhat neglected. A series is reported in which a subdivision is suggested, on the basis of what has been done by other workers, whereby the various mammary pain syndromes are grouped. This is extremely useful, particularly for therapeutic purposes.

[Surgical problem of extensive iliaco-femoral artery obstructions]. / II problema chirurgico delle estese ostruzioni arteriose iliaco-femorali

Extensive iliacofemoral obstruction has always posed a difficult therapeutical problem for the surgeon. Personal experience is cited in support of employment of the deep femoral artery as a natural by-pass, together with its anastomoses. The indications for this form of management are discussed, along with the techniques required. Some personal cases are described.

[Current acquisitions on phlebopathies of the lower extremities]. / Moderne acquisizioni in tema di flebopatie degli arti inferiori

Phlebology has made considerable efforts to free itself from empiricism in recent years. Careful scientific methods have enabled previously unhoped-for results to be obtained in very widespread and debilitating diseases. New and in some cases revolutionary concepts are described, whose application presupposes the existence of well-trained teams. Personal results are also presented.