[Italian study on the treatment of anaemia in chronic dialysis patients switched over to less frequent doses of darbepoetin from human recombinant erythropoietin (rHuEPO)]. / Studio italiano sul trattamento dell'anemia in pazienti in terapia dialitica sostitutiva con darbepoetina alfa con una minore frequenza di somministrazione della dose rispetto all'eritropoietina ricombinante umana (rHuEPO).

BACKGROUND: Darbepoetin alpha is a novel erythropoiesis stimulating protein with unique properties as compared to recombinant human erythropoietin (rHuEPO), including a three-fold longer elimination half-life that allows for less frequent dosing. This study was aimed at testing the efficacy and safety of darbepoetin alpha in a large number of chronic dialysis patients switched from rHuEPO. METHODS: Nine hundred and fifty dialysis patients in stable treatment with rHuEPO were switched to darbepoetin alpha. Patients receiving rHuEPO 2 or 3 times weekly were switched to once weekly darbepoetin alpha and those receiving rHuEPO once weekly were switched to once every other week darbepoetin alpha. Patients received darbepoetin alpha by the same route of administration (SC or IV) as the one used for rHuEPO. The unit doses of darbepoetin alpha (10-150 microg) were titrated to maintain haemoglobin concentration within -1.0 and +1.5 g/dL of the individual mean baseline haemoglobin levels and between 10 and 13 g/dL for 24 weeks. RESULTS: The mean change in haemoglobin from baseline to the evaluation period (weeks 21-24) was statistically but not clinically significant [-0.10 g/dL (95% CI: -0.18, -0.02]. In general, the geometric mean weekly dose of study drug from screening/baseline to evaluation period remained substantially unmodified [(from 26.10 micro g/wk to 25.90 microg/wk; percentage change -0.40% (95% CI: -3.78, 3.10)]. Overall, darbepoetin alpha was well tolerated. CONCLUSIONS: The treatment of anaemia of a large dialysis patient population with unit dosing of darbepoetin alpha is effective and safe in maintaining target haemoglobin concentration at reduced dose frequency.

Spurious estimations of sodium removal during CAPD when [Na](+) is measured by Na electrode methodology.

BACKGROUND: The aim of this study was to investigate the effect of pH and glucose concentration on sodium removal and the dialysate and plasma sodium ratio (D/PNa) as measured by means of a flame photometer (NaF) or direct ion-selective electrode (NaE) in continuous ambulatory peritoneal dialysis (CAPD). METHODS: In vitro, glucose concentration, pH, NaF, and NaE were measured in fresh peritoneal dialysis solutions (PDSs) before and after the addition of glucose or KOH. In vivo, 66 four-hour peritoneal equilibration tests were performed in 35 patients on CAPD using a low pH PDS with a glucose concentration of 3.86%. RESULTS: In vitro, NaF and NaE were significantly influenced by the glucose concentration and pH of the PDS. In vivo, in fresh PDS, there was a significant difference between the NaF and NaE results; the respective median values were 132.1 (interquartile range 129.3 to 137.5) versus 138.0 (134.4 to 141.5) mmol/L (P < 0.0001). The D/PNa ratio calculated by NaE was significantly lower than that calculated by NaF (0.88 +/- 0.03 vs. 0.91 +/- 0.04 and 0. 90 +/- 0.03 vs. 0.94 +/- 0.04 at 60 and 240 min, respectively, P < 0.0001), whereas there was no significant difference between the NaE and NaF values after correction for plasma water and a Donnan factor of 0.96 (0.88 +/- 0.03 vs. 0.88 +/- 0.04 and 0.90 +/- 0.03 vs. 0.91 +/- 0.04, P < 0.3473). Sodium removal was significantly lower when calculated as NaE than when calculated as NaF (43.9 +/- 32.7 vs. 61.0 +/- 32.2 mmol, P < 0.0001). CONCLUSIONS: The fresh PDS sodium concentration can be corrected using a glucose concentration-related factor. The D/PNa ratio calculated as NaE or NaF is not different after correction for plasma water and a Donnan factor of 0.96. Sodium removal must be measured by means of NaF rather than NaE. This could have an important clinical impact.

The role of underlying nephropathy in the progression of renal disease.

BACKGROUND: Disease-specific pathogenic mechanisms may be major determinants of the spontaneous rate of progression of chronic renal failure (CRF). To clarify the role of different underlying renal diseases, we examined the rate of CRF progression in 886 patients with chronic nephropathies. METHODS: Secondary analysis of two multicenter, prospective randomized trials: the Northern Italian Cooperative study (NIC) and the AIPRI study (ACE-Inhibition in Progressive Renal Insufficiency). Univariate and multivariate analyses of variance were used to select the covariates possibly related to CRF progression (estimated by means of the slope of the reciprocal of SCr against time), focusing on the contributory role of primary renal diseases. RESULTS: The overall rate of CRF progression was relatively low but there was a considerable difference in the slopes relating to the underlying nephropathy (particularly evident in the patients with chronic glomerulonephritis (CGN)). The median rate of CRF progression in both studies was more rapid in patients with polycystic kidney disease (PKD) and CGN than in those with other nephropathies. Multivariate analysis showed PKD as an independent predictor of the CRF progression rate only in the NIC Study (P < 0.0015); the selected variables in both studies predicted a variation of only 15-18% in the CRF progression rate. CONCLUSION: The underlying renal disease certainly plays a role in the natural history of CRF, but the variability of the CRF progression rates related to different renal diseases and between individuals with the same diagnosis underlines the need for caution in evaluating risk factors and predicting single patient outcomes.

The renoprotective effect of antihypertensive drugs.

Some antihypertensive drugs may have a renoprotective effect, that is partially independent of their ability to reduce blood pressure. ACE-inhibitors are safe and effective agents that are capable of reducing proteinuria and preventing CRF progression. The results of the AIPRI extension study suggest that they may also have a long-term renoprotective effect. ACE gene polymorphism may partially influence the response to these agents. Angiotensin II receptor 1 antagonists (AT1RA) are effective in reducing proteinuria, but their clinical impact is still a matter of study. It has been shown that non-dihydropyridine and some dihydropyridine calcium channel blockers (CCBs) reduce proteinuria and are also renoprotective, but there is a lack of large-scale prospective randomised trials. Given that the use of various drugs is usually needed to achieve good blood pressure control in patients with CRF, the possibility that a combination of ACE-inhibitors with CCBs or ATIRAs may have an additive renoprotective effect is intriguing.

Low-dosage ibopamine treatment in progressive renal failure: a long-term multicentre trial.

A multicentre trial (11 nephrology centres) was carried out to test the effects of ibopamine, an orally active dopamine-like drug, on the progression of chronic renal failure. For a 2-year period 189 chronic renal failure patients (serum creatinine level 1.5-4.0 mg/dl) were observed. They were homogeneous for basic nephropathy, degree of residual renal function, blood pressure, and proteinuria. The patients were randomly divided into two groups: 96 took ibopamine at a dosage of 100 mg/day (group A) and 93 served as controls (group B). All were on a low-protein diet (mean 0.8 g/kg body weight). By the end of the observation period, the rate of decrease of the renal function indexes in time proved significantly slower (1.8 times) in group A than in group B. The survival curves for renal function (pre-established end points were creatinine level increases equal to or > 20% and equal to or > 40% of the basal values) proved significantly better (p < 0.02 and p < 0.002 respectively) in group A than in group B. The mean plasma creatinine values rose by 17% in group A and by 36% in group B. The creatinine clearance decreased by 5% in treated patients and by 14% in the controls. Statistical analysis ruled out any possible centre effect. The trial suggests that low-dosage ibopamine administration may be used as a valid and safe pharmacological adjunct for retarding the progression of renal failure in patients with mild or moderate chronic renal impairment.

Virological and histological features of hepatitis C virus (HCV) infection in kidney transplant recipients.

BACKGROUND: Although there are some reports regarding prevalence of anti-HCV antibodies in kidney transplant patients, there are scarce data about viraemia, genotyping and liver histology of HCV infection in kidney transplant recipients. METHODS: We studied the prevalence of anti-HCV antibodies by second-generation screening and confirmatory assays in a cohort of 73 renal allograft recipients. All patients were tested for serum HCV RNA using reverse transcription polymerase chain reaction in the 5'-untranslated region (UTR) of the viral genome. HCV RNA positive patients were subjected to genotype analysis using biotinylated type-specific oligonucleotide probes after hybridization with amplified sample material. Eleven of 73 patients showing raised aminotransferase levels underwent hepatic biopsy. RESULTS: Fifteen of 73 (20%) patients were determined anti-HCV positive. Eleven of 73 (15%) showed detectable serum HCV RNA; no viraemic, seronegative patients were identified. Genotyping showed that HCV subtype 2a was dominant (64%), followed by HCV subtypes 1b (27%) and 1a (9%). Six of 11 (54%) HCV RNA patients and 12 of 62 (19%) HCV RNA negative patients showed raised aminotransferase levels (P = 0.03). Liver biopsies showed histological features of chronic hepatitis with mild or moderate degrees of activity. CONCLUSIONS: The prevalence of anti-HCV antibodies and HCV viraemia was 20% and 15% respectively; there was a good association between anti-HCV anti-bodies and HCV viraemia; hepatic enzyme levels were good indicators of ongoing HCV infection; HCV subtype 2a was prevalent; liver histology showed histological characteristics of chronic hepatitis with mild or moderate degrees of activity.

Comparison of second-generation screening and confirmatory assays with recombinant antigens and synthetic peptides against antibodies to hepatitis C virus: a study in renal patients.

The aim of this study was to compare some common tests which are nowadays routinely used to screen and to confirm anti-HCV antibodies in renal patients. There was agreement between Ortho 2 and Abbott 2 in 94% of samples; structural and nonstructural beads of the Abbott supplementary assay were in agreement with 4-RIBA in 98 and in 85% of samples, respectively; 61% of Ortho 2 samples and 65% of Abbott 2 samples were confirmed by 4-RIBA; there was a correlation between semiquantitative analysis of screening tests (Ortho 2 and Abbott 2) and positive results by 4-RIBA; 36 and 33% of Ortho-2- and Abbott-2-positive samples were 4-RIBA indeterminate: in these instances more sophisticated techniques (polymerase chain reaction) (PCR) could be useful as a third-level assay. The comparison between Ortho 2, based on recombinant antigens, and Innotest, based on synthetic peptides, showed agreement only in 44% of samples, but this preliminary comparison cannot afford definitive conclusions. These findings suggest that second-generation assays may sometimes yield conflicting results in renal patients. These contradictions will be resolved by new HCV tests or PCR.

[Diet therapy in preventing the progression of chronic renal insufficiency]. / Terapia dietetica e prevenzione della progressione dell'insufficienza renale cronica.

The effect of a low protein diet (LPD) on the progression of chronic renal insufficiency (CRI) was investigated by reviewing the published studies. Only the trials of Rosman, Ihle and Locatelli fulfilled the main methodological criteria of being randomized, prospective and controlled. They involved 811 patients (671 evaluated: 338 on an LPD, 333 as controls) and had a mean follow-up of 29 months (range 18-48) for an estimated total of about 17,335 patient-months. The only trial whose results showed that LPD had a positive effect on the progression of chronic renal failure (CRF) was Ihle's study with the lowest weight (6.7%) and which involved the most severe CRF; effects limited to the patients with more advanced CRF were found in Roman's study, with an intermediate weight (41.8%); and little effect, if any, in Locatelli's trial accounting for 51.5% of patient-months, with less severe CRI. In conclusion, analysis of published randomized, prospective and controlled trials offers little or no evidence for the hypothesis that an LPD has a greater clinically significant effect on early CRI progression than a controlled protein diet, although a very low protein diet seems to postpone the need for dialysis.

Controlled trials on low-protein diet: effects on chronic renal insufficiency progression.

The effect of a low-protein diet (LPD) on chronic renal insufficiency (CRI) progression was investigated by reviewing the published studies. Only three of these fulfilled the main methodological criteria of being randomized, prospective, and controlled: those of Rosman, Ihle and Locatelli. These trials involved 811 patients (671 evaluated: 338 on a LPD, 333 as controls) and had a mean follow-up of 29 months (range 18-48), for an estimated total of about 17,335 patient-months. The only trial whose results showed that LPD had a positive effect on chronic renal failure (CRF) progression was Ihle's study, with the lowest weight (6.7%) and involving the most severe CRF; effects limited to the patients with more advanced CRF were found in the Rosman study, with an intermediate weight (41.8%); and little effect, if any, was found in the Locatelli trial, accounting for 51.5% of patient-months, with less severe CRI. In conclusion, analysis of published randomized, prospective, and controlled trials offers little or no support for the hypothesis that a LPD has a clinically significant effect on the early CRI progression, although a very low protein diet seems to postpone the need for dialysis.

Kelfiprim versus co-trimoxazole in recurrent and persistent urinary tract infections: multicenter double-blind trial.

Kelfiprim (KP) is a new bactericidal agent containing trimethoprim (T) and sulfametopyrazine (S), a long-acting sulfonamide (ratio 5:4). The posology is one capsule (T 250 mg + S 200 mg) daily, after a loading dose of two capsules on the first day. To evaluate the clinical value of Kelfiprim (KP) vs co-trimoxazole (CO) in urinary tract infection (UTI) a controlled multicenter double-blind trial (MDBT) was carried out in 76 patients suffering from persistent and recurrent UTIs. About 90 per cent response rate (sterile urine at the end of treatment) was obtained for KP and about 85 per cent for CO in recurrent UTI. In persistent UTI the rate of recovery was 66.8 per cent and 53 per cent for KP and CO, respectively. Safety of treatments was excellent in 97 per cent of patients treated with Kelfiprim and 87 per cent treated with co-trimoxazole. Two patients, one in each group, were dropped from the study because of adverse reactions.

Toxicity in man due to stain removers containing 1,2-dichloropropane.

There are reports that 1,2-dichloropropane, a constituent of many commercial solvents and stain removers in Italy, has caused severe liver damage and, sometimes, acute renal failure. Between 1980 and 1983 three cases of 1,2-dichloropropane intoxication (1 by ingestion, 2 by inhalation) were observed. Clinical features included severe liver damage, acute renal failure (2 patients), haemolytic anaemia, and disseminated intravascular coagulation. The most surprising features were haemolytic anaemia and disseminated intravascular coagulation which have not been reported before. The clinical picture was similar despite different modes of exposure.

Sodium kinetics across dialysis membranes.

The kinetics of sodium across dialysis membranes were studied during diffusion and during convection utilizing cuprophan and cellulose hydrate membranes. During diffusion the changes in plasma water sodium concentration are correlated to the sodium concentration gradient between plasma water and dialysate but an increase also occurs when the gradient is annulled, due to the Donnan effect. During convection the plasma water sodium concentration increases during the passage through the dialyzer and the ultrafiltrate sodium concentration is significantly lower than the plasma water sodium concentration; this is due to the fact that the plasma proteins, as anions unable to cross the membrane, affect the kinetics of the sodium cations. Therefore, during diffusion the kinetics of sodium are mainly affected by the sodium concentration gradient and by the plasma protein concentration, while during convection the plasma protein concentration is the main factor affecting the kinetics of sodium.

"Physiological" and "pharmacological" dialysate sodium concentrations.

Forty three uremic patients on regular hemodialysis treatment (4 hours 3 times/week) were dialyzed for a period of 28.95 +/- 14.46 months with a dialysate sodium concentration (NaD) of 142 mEq/l, similar to their plasma water sodium concentration corrected for the Donnan factor ("physiological" NaD). Blood pressure (BP) and body weight (BW) dropped significantly. During two following periods, lasting 18 and 14 months, with NaD 148 mEq/l, similar to the patients' plasma water sodium concentration ("pharmacologically high" NaD), cardiovascular stability improved and BP did not show significant increase. Using "physiological" and "pharmacologically high" NaD the removal of water and sodium by convection improves the cardiovascular stability and the patients' well being, without bringing about the feared long-term cardiovascular side effects, if an appropriate dry body weight is achieved, because of better correction of the cellular overhydration.

Long-term haemodialysis treatment with sodium removal by convection.

Forty-three uraemic patients were studied for 60.95 +/- 14.46 months of haemodialytic treatment (4 hours, 3 times/week). After a first dialysis period of 28.95 +/- 14.46 months with a dialysate sodium concentration (NaD) of 142 mEq/L blood pressure (BP) and body weight (BW) showed values significantly lower (p less than 0.001). During a following period of 32 months with NaD 148mEq/L BP did not show significant changes. A more 'physiological' removal of water and sodium by convection does not bring about the feared long term cardiovascular side effects if an appropriate dry BW is achieved, probably because of better correction of the cellular overhydration.

Steroid pulses and plasmapheresis in the treatment of acute renal failure in multiple myeloma.

Four patients with acute renal failure due to myeloma (IgG with lambda, lambda, lambda, IgG with kappa) were studied; serum creatinine was 4.7, 5.9, 4.25, 10.8 mg%, and proteinuria 2.1, 2.8, 5.2, 4.2g/24h respectively. Renal biopsy specimens (3 patients) showed interstitial fibrosis, oedema, infiltration of mononuclear cells, tubular atrophy or dilatation with many 'myeloma kidney' casts. The patients were treated with plasmapheresis (2-4 exchanges) and methylprednisolone pulses (three to four 1g pulses). Maintenance therapy included prednisone, vincristine, melphalan and cyclophosphamide. After a follow up of 26, 17, 8, 6 months respectively, serum creatinine levels are 1.7, 2.4, 1.8, 4.2mg% respectively. Proteinuria disappeared after three months of therapy in 3 patients, and then remained absent for the successive follow up.