[Prevention of HCV infection in the hemodialysis setting]. / Prevenzione dell'infezione da HCV in emodialisi.

The discovery of hepatitis C viruses in the 1990s started a new era in hemodialysis. Hepatotropic RNA viruses are able to infect the immune cell populations of the host and show high viral persistence and chronicity rates. Although, like the HIV viruses, they can change inside the host, they are less resistant than hepatitis B viruses both to environmental conditions and common disinfection tools. The clinically subtle course of chronic and acute infections has pivotal importance in the spread of HCV and can explain its prevalence rates of 2-3% in the general population and about 9% in hemodialysis patients. Among the risk factors for transmission, the nosocomial risk is of primary importance in the hemodialysis setting but it is present in every health-care environment. Though low, also the occupational risk is important, particularly for nurses, in whom accidental pricks are responsible for a mean incidence of HCV infection of 1.8%. In the dialysis setting both these risk factors are essentially imputable to sanitary malpractice. In the last 30 years, the most important agencies for the prevention of infection have developed a set of "special" precautions for particular settings such as hemodialysis. In this review we report and recommend these precautions because their regular adoption is fundamental and a sufficient requisite to prevent the spread of hematogenous infections, including HCV.

[Natural history of HCV infection and risk of death in a cohort of patients on long-term hemodialysis]. / Storia naturale dell'infezione da HCV e rischio di morte in una coorte di pazienti in emodialisi da lungo tempo.

BACKGROUND: HCV infection represents the major cause of chronic liver disease in hemodialysis and renal transplant patients. The clinical course of liver disease in hemodialysis patients is generally asymptomatic. Only few studies describe the natural history of HCV infection in haemodialysis patients, showing an association between HCV infections and poor survival. METHODS: A prospective cohort study of our haemodialysis population was conducted to define the natural history of HCV infection and its relation to mortality. 77 patients on haemodialysis were enrolled, 24 (31%) of whom were anti-HCV and 53 (69%) anti-HCV-negative. RESULTS: The HCV-RNA was positive in 18 of the 24 anti-HCV-positive subjects (75%). None of the anti-HCV-negative subjects was HCV-RNA-positive. Eight of the 18 HCV-RNA-positive patients (40%) developed cirrhosis with portal hypertension and ascites within 7 years after the first increase of GPT. Seven of these died, nobody developed hepatocarcinoma (HCC). During 58+/-37-follow-up months mortality rate was higher among anti-HCV-positive patients than among anti-HCV-negative. Besides, the 6 deaths occurred only among anti-HCV-positive and HCV-RNA-positive patients. CONCLUSION: in our haemodialysis patient population the presence of antibodies anti-HCV and HCV-RNA is associated with an increased risk of developing liver cirrhosis and of death, in comparison to anti-HCV-negative patients. Our data show that anti-HCV-positive patients have an accelerated course towards chronic hepatopathy and cirrhosis.

Clinical pathological correlates of renal biopsy in elderly patients.

BACKGROUND: Reports have shown that well-defined histological patterns do not always correspond to equally clear clinical pictures, particularly so in elderly patients. METHODS: With the aim of assessing clinicopathological correlations in the population aged >65 years with that of lower age, we retrospectively analyzed computerized records of renal needle biopsies consecutively performed in the decade 1991-2000 in our unit. RESULTS: Among the 392 eligible subjects, there were 150 patients 65 years of age and more, 76 of whom were over 70. The average serum creatinine was 2.9 mg/dl, with values > 3.5 mg/dl in 25% of cases. The major indication to biopsy was nephrotic syndrome followed by chronic renal failure both in the young adult and the elderly population. The rapidly progressive form led more often to renal biopsy in the elderly patients, and the different prevalence was statistically significant (p < 0.05), as was the higher prevalence of urinary anomalies in the young-adult population. Regarding renal histology, the crescentic necrotizing forms were significantly more frequent in the elderly patients, while IgAN, minimal change disease and SLE predominate in young adults. The most relevant result is the greater prevalence of crescentic necrotizing glomerulonephritis in elderly patients, not only in the cases presenting clinically as rapidly progressive renal failure and acute renal failure, but also in those with the clinical picture of chronic renal failure. CONCLUSIONS: Re-evaluation of our case files verifies the importance of the bioptic approach in selected cases with stages 3-4 chronic kidney damage. This holds true especially for elderly patients.

[On-line hemodiafiltration without acetate]. / L'emodiafiltrazione on-line senza acetato.

PURPOSE: The suitably filtered dialysate which is currently reinfused during on-line hemodiafiltration (HDF-OL) contains bicarbonate and small doses of acetate. The trend of acetataemia During "forced" convective treatments has never been studied. The gain in acetate secondary to the considerable quantities of fluids infused might have clinical significance in relation to the well-known side effects of this anion. METHODS: In this pilot study 12 patients underwent HDF-OL with reinfusion in predilution of 40 L of substitution fluids containing or not 3 mmol/L of acetate. Apart from this variable, all the other treatment parameters were the same in both procedures. The treatments were carried out in two short consecutive intervals in a random sequence. RESULTS: During HDF-OL the use of dialysate containing small doses of acetate is associated with levels of acetataemia 5-6 times higher compared to the basal. HDF-OL without acetate cancels out this increase. The acetate gained by the patients is significant, on average 75 mmol, and accounts for over 1/3 of the global base gain. Consequently, the bicarbonataemia levels at the end of treatment are significantly higher in HDF-OL with acetate than in the treatment without. Two hours after the end of the treatments the IL-6 levels tend to grow in both methods, but numerically less in HDF-OL without acetate; the difference verges on meaningfulness. CONCLUSIONS: The acetate gain is significant during forced convective treatments carried out with standard dialysate. This acetate gain can trigger cytokinin activation. These events are cancelled out by eliminating the acetate from the dialysate. The absence of this anion will be compensated with appropriate increases in the concentration of bicarbonate in the dialysis fluid.

Age dependency of myocardial structure: a quantitative two-dimensional echocardiographic study in a normal population.

Histological changes of the myocardium occur with aging due to an increase in collagen content, hypertrophy of fibers, and patchy fibrosis. Quantitative analysis of conventional echocardiographic images provides an in vivo assessment of myocardial structure by the evaluation of the gray level distribution; with this technique, a relation between myocardial fibrosis and pathological ultrasonic response has been documented. The aim of this study was to evaluate the relation between ultrasonically assessed myocardial structure and age in a normal population. Seventy-eight subjects (47 men; mean age, 51 years; age range, 23-87 years) without apparent cardiovascular and systemic disease underwent conventional two-dimensional echocardiographic examinations. Still frames at end-diastole from apical four-chamber view were digitized and converted in matrices of 256 x 256 pixels. First-order statistical analysis was performed to describe a region of interest in the interventricular septum. The following parameters were studied: mean (gray level amplitude), standard deviation (overall contrast), uniformity (tonal organization), and entropy (tendency of gray levels to be spread). Myocardial structure was assessed in 75 of 78 subjects, divided into three groups: I, age 23-40 years; II, age 41-65 years; and III, > 65 years. Significant differences for all the parameters were found between the age groups. Age correlated directly with mean and entropy (r = 0.77 and 0.69, respectively) and inversely with uniformity (r = 0.70). Our results suggest that quantitative echocardiography can reveal age-related changes in myocardial structure that are characterized by a greater echogenicity and loss in tonal organization, possibly due to increased collagen content within the fibers.

Cardiovascular stability during haemodialysis, haemofiltration and haemodiafiltration.

Several comparative studies have claimed that procedures based substantially or exclusively on pressure-driven water-solute transport, such as haemodiafiltration or haemofiltration, afford better protection of the cardiovascular tolerance to fluid removal than conventional haemodialysis. During each depurative modality, several factors are set in motion that might impact, each in its own right, upon the haemodynamic response to fluid withdrawal. To explore the haemodynamic effect of each of them singularly, one needs to keep all other components unvaried. However, this is very difficult to accomplish. For instance, to confirm the alleged greater protection of cardiovascular stability by pure convection vs diffusion, one needs to keep unvaried all the other factors potentially affecting haemodynamic tolerance, i.e. the rate of body fluid removal, the membrane, the buffer, the blood temperature in the extracorporeal circuit, depuration efficiency, the sodium balance, the fluid sterility and so on. Such studies are still awaited. However, clinical trials published to date have not resolved the question of whether haemofiltration and haemodiafiltration provide a better haemodynamic tolerance to fluid removal. If we limit our consideration to controlled trials only, most prospective studies have adopted a cross-over design implemented on very small patient samples and for very short periods. Such an approach is liable to generate misleading results because the incidence of dialysis hypotension often fluctuates from time to time. Owing to such fluctuations, results can be strongly affected by the 'order effect' of the cross-over from one technique to the other. The negative results provided by parallel comparisons of procedures should be taken with caution because patients samples did not include a suitable proportion of unstable patients.

Impaired sympathetic response before intradialytic hypotension: a study based on spectral analysis of heart rate and pressure variability.

The purpose of this study was to evaluate the autonomic response to standard haemodialysis and the changes associated with the onset of intradialytic hypotension in 12 normotensive patients with uraemia. Power spectra of R-R interval and of blood pressure fluctuations were obtained during a standard dialysis session and estimated in the low-frequency (LF, 30-150 mHz) and high-frequency (HF, 150-400 mHz) range. The absolute power of the LF component of blood pressure variations and the LF/HF ratio of R-R interval were assumed as indexes of sympathetic activity. Standard haemodialysis induced hypotension in six patients (unstable) while a minor pressure decline was present in the other six (stable). Normalized blood volume before dialysis and percentage volume reduction were similar in the two groups. Tachycardia in response to pressure and volume decrease was more pronounced in stable than in unstable patients, as evidenced by a higher slope of the relation between R-R interval and systolic blood pressure (7.9 versus 0.9 ms/mmHg, P<0.01). Sympathetic tone was enhanced during early dialysis in all patients (+2+/-1 for R-R LF/HF ratio, +2.4+/-0.6 mmHg2 and +7.2+/-2 mmHg2 for absolute LF power of diastolic and of systolic blood pressure respectively, P<0.05), compared with baseline predialysis values. During late dialysis, unstable patients showed an impairment of sympathetic activation which preceded hypotension and was maximal during the crisis (-2.9+/-1.4 for R-R LF/HF ratio, -2.7+/-1.4 mmHg2 and -8.6+/-4.0 mmHg2 for absolute LF power of diastolic and of systolic blood pressure respectively, P<0.05). On the contrary, stable patients showed constantly elevated indexes (+3.7+/-1.4 for R-R LF/HF ratio, +5.9+/-2.7 mmHg2 and +13.3+/-6.2 mmHg2 for LF of diastolic and of systolic blood pressure, P<0.05). Values returned to predialysis levels after the end of the dialysis session in all patients. We conclude that standard haemodialysis activates a marked and reversible sympathetic response in both stable and unstable uraemic patients. However, in unstable patients, such activation is impaired in late dialysis, therefore contributing to the onset of the hypotensive crisis.

Hepatitis C virus infection and acute or chronic glomerulonephritis: an epidemiological and clinical appraisal.

BACKGROUND: The relationship between hepatitis C virus (HCV) infection and acute or chronic glomerulonephritis (GN) is not well understood. METHODS: Two hundred and eighty-four patients with biopsy-proven GN and other renal diseases were studied in a multicentre survey performed during the period 1992-1995. Several clinical parameters were collected for each patient at the time of renal biopsy. We made a multivariate analysis by logistic regression model to evaluate the independent association of clinical and histological patient characteristics with HCV infection, as detected by anti-HCV antibody testing. In addition, three patients with HCV-related liver disease, membranous nephropathy, and proteinuria in the nephrotic range received therapy with interferon-alpha in standard doses. RESULTS: The prevalence of anti-HCV positivity was 13% (38/284). The frequency of anti-HCV positivity ranged between 0 and 100% in the different types of renal diseases, the difference was statistically significant (P = 0.0001). The anti-HCV rate was significantly higher in patients with cryoglobulinaemic membranoproliferative and mesangioproliferative GN than among the other individuals (14/14 (100%) vs 24/270 (9%), P = 0.0002). Our multivariate analysis by logistic regression model showed that age (P = 0.0017) and type of renal diseases (P = 0.0007) were independently and significantly associated with anti-HCV antibody. At the completion of treatment with interferon-alpha, 67% (2/3) of patients with membranous nephropathy had lowering of hepatic enzyme levels into the normal range whereas 100% (3/3) of these did not show significant reduction of proteinuria. CONCLUSIONS: We observed strong association between HCV infection and cryoglobulinaemic GN. Age and type of renal disease were important independent predictors of anti-HCV positivity in our cohort of patients. Three anti-HCV-positive patients with membranous nephropathy did not show significant remission of nephrotic proteinuria after treatment with interferon-alpha. Our data do not appear to support an association between HCV and non-cryoglobulinaemic GN. Further epidemiological surveys, experimental studies and clinical trials are warranted to fully elucidate the role of HCV in non-cryoglobulinaemic GN.

Signal-averaged ECG abnormalities in haemodialysis patients. Role of dialysis.

BACKGROUND: Late potentials (LP) on the signal-averaged electrocardiogram (SAECG) are predictive of malignant ventricular arrhythmias and sudden cardiac death in patients with ischaemic and non-ischaemic cardiomyopathy. Cardiac dysfunction, both regional and global, as well as supraventricular and ventricular arrhythmias are reported in a high percentage of patients with end-stage renal failure (ESRF). The aim of the study was to assess the prevalence of LP and the effects of haemodialysis on the SAECG of ESRF patients. METHODS: SAECG was recorded immediately before and within 30 min after the end of dialysis in 48 patients in sinus rhythm, free of conduction disturbances on ECG and of signs of congestive heart failure. Serum electrolytes were sampled together with the SAECG recordings. An echo-Doppler exam was performed within 2 weeks of the study. SAECGs were adequate for analysis in 45/48 patients. LP were present when at least two of the following criteria were fulfilled: QRS duration < or = 115 ms, LAS40 < or = 38 ms, RMS40 > or = 38 microV at 40 Hz high pass bidirectional filter, and noise <0.7 microV. RESULTS: LP were detected in 12/45 patients (25%) on the SAECG before dialysis; of these 12 patients, seven had a history of a previous myocardial infarction and two had documented coronary artery disease (CAD). A significant greater wall motion score index--calculated on a 16 segment model--was reported in patients with LP (1.20+/-0.20 vs 1.01+/-0.03, P<0.01), while left ventricular mass was comparable in the two groups of patients. At the end of dialysis, a significant prolongation of fQRS duration was found both at 25 and 40 Hz filters (from 98+/-11 to 106+/-16 ms and from 97+/-12 s to 102+/-13 ms, respectively, P<0.001). A significant inverse relationship was seen between the percentage of dialysis-induced serum potassium reduction and fQRS changes at 40 Hz (r=-0.68, P<0.001). CONCLUSIONS: LP were detected in a significant proportion of dialysis patients, probably related to underlying CAD with left ventricular dysfunction. Prolongation of fQRS after dialysis could be explained by the acute reduction in serum potassium levels.

Convective treatments with on-line production of replacement fluid: a clinical experience lasting 6 years.

BACKGROUND: The introduction of techniques with on-line (OL) production of replacement fluid by filtration of dialysis fluid raises concerns about exposure of dialysis patients to pyrogenic substances. This work was undertaken to evaluate safety and feasibility of OL preparation of replacement fluid for haemodiafiltration (HDF). METHODS: OL HDF was carried out with commercially available monitors without any adjustment in the operational organization of our Centre. Bicarbonate dialysis fluid was filtered twice before being reinjected into the patients. The effects of acute load of OL fluid were assessed by very sensitive in vitro and in vivo tests; the chronic effects were assessed by monitoring the patients for the appearance of any untoward clinical manifestations and by measuring their cytokine response. RESULTS: In a pilot study the membrane filter culture technique of replacement fluid yielded no bacteria or mycetes growth, while LAL test was < 0.01 EU/ml. The normal human monocyte production of TNF alpha, IL-1 beta and IL-1Ra was not significantly different when cells were incubated with OL or commercial replacement fluid. The patients' body temperature profile (continuous recording during treatments and the following 24 h) overlapped with that of the control procedure. Over 6 years we performed 4284 OL treatments (total amount reinjected fluid 102,900 litres) on 13 patients treated for 26 +/- 9 months. In none of these treatments did we observe pyrogenic reactions. In comparison with the previous period on standard bicarbonate haemodialysis, OL HDF afforded significantly better cardiovascular tolerance to fluid removal and higher Kt/V values. The nutritional status did not deteriorate, while the acute-phase reactants and serum beta 2M levels did not increase. Moreover, no translucent cysts or destructive arthropathy were observed on bone X-rays. The patients' plasma cytokine levels and monocytes cytokines production, measured either before or after a single OL HDF, were comparable with the values obtained in controls treated with standard HDF. CONCLUSIONS: We conclude that OL-prepared replacement fluid is as safe as that of the commercial bags with regard to sterility and non-pyrogenicity. OL HDF can be readily implemented in any dialysis centre without bringing any further burden on the staff.

Characterization of myocardial tissue in patients undergoing maintenance hemodialysis by quantitative echocardiography.

The uremic state affects myocardial structure, bringing about, among other things, interstitial calcium deposition. Abnormalities of myocardial structure can be assessed quantitatively and noninvasively during life by the analysis of the gray-level distribution of conventional two-dimensional echocardiograms. The aim of this study was to evaluate the role of quantitative echocardiography in providing information on myocardial structure in patients under maintenance hemodialysis and to relate the ultrasonic findings with abnormalities in calcium-phosphate metabolism. Forty patients undergoing dialysis without abnormalities in left ventricular regional and global function and 17 hypertensive patients with comparable left ventricular hypertrophy were studied. The distribution of the gray levels within a region of interest in the interventricular septum was analyzed off-line by an array processor-based computer. Compared with hypertensive patients, patients undergoing dialysis showed a greater myocardial echogenicity (mean 92 +/- 20 versus 72 +/- 15; p = 0.004) and a reduced homogeneity of distribution of gray levels (entropy 4.5 +/- 0.2 versus 4.2 +/- 0.2, p < 0.01; uniformity 0.010 +/- 0.003 versus 0.020 +/- 0.004, p < 0.005). In the same patients, a significant negative linear relation was found between entropy and calcium-phosphate product (r = -0.66; p = 0.001). Quantitative analysis of conventional two-dimensional echocardiograms allows the detection of a pathologic myocardial structure in patients under maintenance hemodialysis with normal left ventricular function. These abnormalities are related to disorders of calcium-phosphate metabolism and bear no relationship to the degree of left ventricular hypertrophy.

Non-invasive monitoring of hemodynamic parameters during hemodialysis.

We studied in 13 hemodialysis patients intradialytic variations of blood volume (BV) and cardiac output, by means of non-invasive methods. We found a weak correlation, r 0.2 or less, between BV variations and intradialysis blood pressure variations. The sensitivity of the former in describing the variations of the latter was only 32%. During the 30 min preceeding the hypothensive crisis the percent BV variations did not show any predictive trend. On the contrary, refilling increased as blood pressure dropped and a weak inverse relation (r -0.35) was found between these two parameters. Unstable patients had predialytic blood volume values significantly lower than stable ones and comparable to healthy subjects. On the contrary, the correlation between percent variations of cardiac output index and MAP was 0.68 with a sensitivity and specificity of 90% and 59%, respectively. Unfortunately these promising results were obtained only with an estimate of cardiac output obtained by echocardiography and not by transthoracic impedance cardiography, which is much more feasible than the former as on-line monitoring of cardiac output. On-line monitoring of hemodynamic parameters is an appealing but still unsolved task.

Thermal balance and dialysis hypotension.

Many studies have confirmed our original observation that dialysate T set at about 35 degrees C affords a better hemodynamic protection than the standard dialysate T of 37-38 degrees C. In this review we present some new data on the hemodynamic mechanism of the protective effect of cold dialysis on blood pressure. The study was based on serial assessment of the percent changes occurring during dialysis treatment in estimated stroke volume (aortic blood flow determined by Doppler echocardiography), blood volume (hemoglobinometry), arterial pressure (Dynamap), and heart rate (ECG), from which cardiac output (CO) indexes and total peripheral vascular resistances (TPVR) were derived. Of the 14 pts studied, 7 showed a drop in mean arterial pressure (MAP) of 25% or greater during standard dialysis (unstable patients). Compared with the 7 patients having more stable intradialysis MAP, unstable pts showed greater reduction in CO which was disproportionately greater than the reduction in blood volume, and a paradoxical decrease in TPVR, the difference being highly significant (p < 0.01 for both changes). When crossed-over to cold dialysis, along with a significantly lower reduction in MAP (p < 0.01) the unstable pts showed a lower decrease in CO which paralleled the reduction in blood volume, and an increase in TPVR. These changes were highly significant (p < 0.01). Data suggest that dialysis hypotension is characterized by an impaired venous return, probably due to the peripheral blood pooling (increased ratio between the 'unstressed' and 'stressed' blood volume) associated with the decrease in TPVR. Exposure of extracorporeal blood to cold dialysate favours the venous return to the heart by increasing TPVR and the 'stressed' blood volume.

Circulating growth hormone and insulin-like growth factor-I in nonalcoholic liver cirrhosis with or without superimposed hepatocarcinoma: evidence of an altered circadian rhythm.

Adult liver is considered the major source of circulating insulin-like growth factor-I (IGF-I). Growth hormone (GH) exerts its effects by stimulating IGF-I release from the liver, which then mediates the somatogenic actions in target tissues. In turn, circulating IGF-I levels operate a negative feedback mechanism on GH release. In cirrhotic patients, single daily determinations, performed after an overnight fast, indicated that serum IGF-I are decreased, whereas GH levels are increased. To verify whether this phenomenon occurs through the 24-h period, we have studied the profiles of GH and IGF-I in cirrhotic patients with or without superimposed hepatocellular carcinoma (HCC) and in a group of control subjects. The results of the present studies suggest that in cirrhotic patients, the above changes are constantly present through the 24-h period, and are associated with a loss of circadian rhythm for both GH and IGF-I. These data are consistent with a failure of the liver to synthesize and release IGF-I in response to GH. In addition, the presence of constantly higher IGF-I levels in cirrhotic patients with superimposed HCC, compared with cirrhotic patients without HCC, raises the hypothesis of a causal relationship between IGF-I and the development of HCC.

[Ursodeoxycholic hemisuccinate in the treatment of chronic active hepatitis. A controlled clinico-therapeutic study]. / L'emisuccinato dell'acido ursodesossicolico nel trattamento dell'epatite cronica attiva. Studio clinico-terapeutico controllato.

This controlled study was performed on 36 patients affected by HBV and/or HCV correlated chronic hepatitis (CAH). Eighteen of them received 300 mg of UDCA-hemisuccinate orally twice a day for six months; the other 18 received 200 mg of S-adenosyl-methionine (SAMe) twice a day for six months. The two groups were determined randomly. Treatment with UDCA-hemi-succinate produced a statistically significant reduction in ALT (from 167 +/- 17 to 119 +/- 15 U/l; p < 0.0001), AST (from 122 +/- 14 to 86 +/- 11 U/l; p < 0.0001) and y-GT (from 81 +/- 10 to 53 +/- 6 U/l, p < 0.0001). The results obtained suggest that UDCA-hemi-succinate may be useful in the long-term treatment of chronic liver diseases of viral aetiology because it improves the biochemical parameters of hepatocellular necrosis and/or increased liver cell permeability.