Mariarosaria Campise

Benefits and risks of protracted treatment with human recombinant erythropoietin in patients having haemodialysis

Fourteen patients with uraemic anaemia and having regular haemodialysis were given human recombinant erythropoietin in increasing doses, beginning with 24 U/kg thrice weekly. One patient was dropped from the study because of recurrent thrombosis of vascular access sites. In the other 13 patients, followed up for a mean of 9.1 months (range 8-11), haemoglobin concentrations increased from 62 (SD 8) to 105 (9) g/l. No antierythropoietin antibodies were detected during the study. The correction of anaemia was associated with a tendency to hyperkalaemia and a mild increase of unconjugated bilirubinaemia. In eight previously hypertensive patients antihypertensive treatment had to be reinforced, but in normotensive patients blood pressure did not change. Thrombosis of arteriovenous fistulas occurred in two patients and a cerebral ischaemic lesion in one. Protracted treatment with human recombinant erythropoietin evidently can maintain normal haemoglobin concentrations in uraemic patients over time. Full correction of anaemia, however, may trigger some vascular problems, particularly in hypertensive patients and those with a tendency to thromboembolism.

No association of converting enzyme insertion/deletion polymorphism with immunoglobulin A glomerulonephritis☆

It has been recently reported that in type 1 diabetes the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme gene is associated with the presence of diabetic nephropathy. Tissue angiotensin I-converting enzyme is determined by I/D polymorphism, and it has been speculated that in diabetes differences of local angiotensin II availability determine the risk of renal disease. Since angiotensin II is thought to play an important role in the evolution of renal disease in general, we tested whether genotype distribution of the I/D polymorphism is also different in patients with immunoglobulin A-glomerulonephritis (IgA-GN). Furthermore we compared IgA-GN patients with (1) stable renal function or (2) terminal renal failure to investigate a potential role of the I/D polymorphism in the renal prognosis. We examined 122 patients with biopsy-confirmed IgA-GN who had stable renal function and 82 dialysis-dependent or transplanted patients with biopsy-confirmed IgA-GN. Furthermore, in 134 healthy individuals used as controls we analyzed the DNA for normal distribution of genotypes and allele frequencies. The polymorphic region was amplified using polymerase chain reaction with specific primers. Alleles were detected on 2% agarose gels. Genotype distributions and allele frequencies were not significantly different between controls and patients with IgA-GN and stable renal function. Furthermore, no significant difference in genotype distribution was detected between patients with IgA-GN and stable renal function compared with patients with IgA-GN and end-stage renal failure, although a trend for a higher frequency of DD-homozygotes was noted in the latter group (P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Oxidative stress in kidney transplant patients.

Background. Little information is available about the role of oxidative stress in renal transplant patients. To evaluate the prevalence and severity of oxidative stress in renal transplantation, the authors conducted a cross-sectional study. Methods. In 112 cadaver or living-donor kidney transplant recipients with a follow-up of at least 6 months and with plasma creatinine less than or equal to 2.5 mg/dL, complete blood count, serum vitamin B12, serum folate (s-F), reactive oxygen species (ROS), thiol groups (−SH), total antioxidant activity (TAOC), serum homocysteine (Hcy), and intraerythrocyte folate (ery-F) were measured. Results. The mean levels of Hcy (21.1 &mgr;M vs. <10 &mgr;M), ROS (302.7 U. Carr (Carratelli units) vs. 250–300 U. Carr), and TAOC (410.6 &mgr;mol/HclO/mL vs. >350 &mgr;mol/HclO/mL), were higher than the reference interval, whereas −SH groups, vitamin B12, s-F, and ery-F were within the normal range. In the multivariate model, plasma creatinine (P =0.0062), vitamin B12 (P =0.0121), and TAOC (P =0.0007) were independently associated with oxidative stress. At multiple regression analysis, −SH groups and ROS were directly and inversely related to hematocrit (P =0.0007 and P =0.0073). There was also a negative correlation between −SH groups and blood pressure levels (P =0.0095). Conclusions. Renal transplant patients have a pattern of increased oxidant stress that is counterbalanced by an enhancement of the antioxidant mechanisms. Besides the well-known risk factors, the authors found that anemia is an independent risk factor for an increase of ROS. Further studies are needed to evaluate whether the correction of anemia might prevent or reduce the oxidative stress in renal transplant patients.

Atrial Natriuretic Peptide and Hemodynamic Changes During Normal Human Pregnancy

We compared plasma atrial natriuretic peptide (ANP) and cGMP levels during normal pregnancy--a condition characterized by hypervolemia, high cardiac output, and decreased vascular resistance--with postpartum levels and assessed their relation to pregnancy-induced hemodynamic changes. Humoral and hemodynamic variables were measured in healthy women subjects in the supine and upright postures at each trimester of pregnancy and postpartum. Supine plasma ANP was increased throughout pregnancy (32 +/- 5, 21 +/- 3, and 19 +/- 2 versus 15 +/- 1 pmol.L-1, respectively, at each trimester versus postpartum), as was cGMP (8.6 +/- 1, 7.1 +/- 1, and 6.6 +/- 1 versus 5.6 +/- 1 nmol.L-1), and their increments were directly related (r = .68, P < .01). Both ANP and cGMP levels did not differ from postpartum levels after subjects stood. Supine stroke volume was initially increased but declined below postpartum levels in late pregnancy (69 +/- 4, 60 +/- 3, and 44 +/- 3 versus 58 +/- 4 mL.m-2), whereas after subjects stood it was always higher (56 +/- 3, 58 +/- 3, and 49 +/- 2 versus 44 +/- 2 mL.m-2); thus, stroke volume tended to increase in response to standing in late pregnancy. Supine cardiac index had a similar trend, which was opposite to that of total peripheral resistance (1213 +/- 62, 1265 +/- 79, and 1729 +/- 89 versus 1654 +/- 92 dyne.s-1.cm-5.m-2).(ABSTRACT TRUNCATED AT 250 WORDS)

Is cyclosporine in renal-transplant recipients more effective when given twice a day than in a single daily dose?

Background. It is still unknown whether it is better to administer cyclosporine (CsA) once or twice a day to renal-transplant patients. Methods. Fifty-four patients were randomized to receive CsA once a day (OD group, 28 patients) or twice a day (BD group, 26 patients). Clinical parameters and pharmacokinetic studies were regularly monitored over the first year. Results. Two patients lost their grafts because of renal vascular thrombosis. A patient in the BD group died. The other 51 patients were alive with graft functioning after a minimum follow-up of 1 year. Five patients per group had reversible acute rejection. There was a not significant trend toward a lower mean serum creatinine in OD than in BD (1.38±0.38 and 1.7±0.80 mg/dL at 1 year posttransplant, respectively). In 47 patients, 319 pharmacokinetic studies were performed. We measured the area under the concentration-time curve during the first 4 hours (AUC0–4) and CsA blood levels at 0, 2, and 4 hours after dosing. C0 was significantly lower in OD than in BD (P=0.0011), whereas C2 (P<0.0001) and C4 (P<0.0001) were significantly higher in OD than in BD. In OD, the AUC was higher than in BD (P<0.0001). OD allows us to reach high levels of C2 and AUC for several hours after dosing, whereas BD showed persistently high levels throughout the whole day. Conclusion. No difference in survival and rejection rates were observed between OD and BD groups.

Treatment of Uraemic Anaemia with Recombinant Human Erythropoietin

Several factors have been involved in the pathogenesis of uraemic anaemia: inhibition of erythropoiesis and hyperhaemolysis to uraemic toxins (1); iron deficiency due to blood losses in the extracorporeal circuit (2); severe hyperparathyroidism with osteitis fibrosa (3) ; abnormally high concentrations of aluminium (4). However, there is general agreement that the main cause of uraemic anaemia is the insufficient production of erythropoietin from the diseased kidneys (5).

Appropriate Endpoints for Renal Transplantation Clinical Trials

The patient and graft survival are the primary endpoints to evaluate safety and efficacy of the immunosuppressive treatments in renal transplantation. Today, however, the results are so good that a huge number of patients is needed to find statistically significant differences between treatments. Secondary endpoints are, therefore, used. Infections and other side effects are good endpoints for safety. Acute rejection is the best surrogate endpoint for efficacy. The diagnosis of acute rejection rests on an increase of plasma creatinine but how much the increase should be to define rejection is still unclear. Moreover, a number of noninvasive techniques can be used to exclude causes of graft dysfunction other than rejection. Thus, renal biopsy may be required to confirm the diagnosis. The severity of acute rejection may be used as a tertiary endpoint, but the criteria for assessing the severity of rejection still need to be standardized either based on clinical or histological variables.