Type 2 diabetes treatment and progression of chronic kidney disease in Italian family practice.

AIMS: Progressive chronic kidney disease represents a dreadful complication of type 2 diabetes mellitus (T2DM). We tested the pattern of use and the renal effects of old glucose-lowering drugs in T2DM patients cared for by Italian general practitioners (GPs). METHODS: Data of 2606 T2DM patients were extracted from the databases of GPs, who do not have access to the most recent glucose-lowering drugs in Italy. The rate of kidney function decline was calculated by CKD-EPIcr, based on two consecutive creatinine values. RESULTS: Metformin was used in 55% of cases, either alone or with sulfonylureas/repaglinide, across the whole spectrum of CKD (from 66% in stage G1 to only 8% in G4). Sulfonylurea use peaked at 21-22% in stage G2-G3a, whereas repaglinide use significantly increased from 8% in G1 to 22% in G4. The median rate of CKD decline was - 1.64 mL/min/1.73 m2 per year; it was higher in G1 (- 3.22 per year) and progressively lower with CKD severity. 826 cases (31.7%) were classified as fast progressors (eGFR decline more negative than - 5 mL/min/1.73 m2 per year). The risk of fast progressing CKD was associated with increasing BMI, albuminuria, and sulfonylurea use, alone (OR, 1.47; 95% confidence interval, 1.16-1.85), or in association with metformin (OR, 1.40; 95% CI 1.04-1.88). No associations were demonstrated for metformin, cardiovascular and lipid lowering drug use. CONCLUSION: In the setting of Italian family practice, sulfonylurea use is associated with progressive CKD in patients with T2DM. Metformin, at doses progressively reduced according to CKD stages, as recommended by guidelines, is not associated with fast progression.

[Effects of dose of erythropoiesis stimulating agents on cardiovascular outcomes, quality of life and costs of haemodialysis. the clinical evaluation of the DOSe of erythropoietins (C.E. DOSE) Trial]. / Effetti della dose degli agenti stimolanti l'eritropoiesi su esiti cardio-cerebrovascolari, qualità di vita e costi in emodialisi.

BACKGROUND: Anaemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are the most used treatment option. In observational studies, higher haemoglobin (Hb) levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to Hb levels around 9-10 g/dL. Randomized studies found that targeting higher Hb levels with ESA causes an increased risk of death, mainly due to adverse cardiovascular outcomes. It is possible that this is mediated by ESA dose rather than haemoglobin concentration, although this hypothesis has never been formally tested. METHODS: We present the protocol of the Clinical Evaluation of the Dose of Erythropoietins (C.E. DOSE) trial, which will assess the benefits and harms of a high versus a low ESA dose therapeutic strategy for the management of anaemia of end stage kidney disease (ESKD). This is a randomized, prospective open label blinded end-point (PROBE) design trial due to enroll 900 haemodialysis patients. Patients will be randomized 1:1 to 4000 UI/week i. v. versus 18000 UI/week i. v. of epoetin alfa, beta or any other epoetin in equivalent doses. The primary outcome of the trial is a composite of cardiovascular events. In addition, quality of life and costs of these two strategies will be assessed. The study has been approved and funded by the Italian Agency of Drugs (Agenzia Italiana del Farmaco (AIFA)) within the 2006 funding plan for independent research on drugs (registered at www.clinicaltrials.gov (NCT00827021)).

Efficacy and (pharmaco)kinetics of one single dose of rasburicase in patients with chronic kidney disease.

AIMS: Hyperuricemia is a risk factor associated with cardiovascular and renal disease. Recently, rasburicase, a recombinant urate oxidase, has been developed for the treatment of hyperuricemia in patients with primarily hematological malignancies. We studied the pharmacokinetics and metabolism of rasburicase in the treatment of chronic asymptomatic hyperuricemia in chronic kidney disease (CKD) patients. MATERIALS AND METHODS: We studied 9 CKD patients with hyperuricemia, whose mean serum acid concentration was 10.2 (range 8.3-15.8) mg/dl. No study subject was taking allopurinol (3/9 are allopurinol intolerant). Patients were treated with rasburicase (0.2 mg/kg/day) in single dose by intravenous infusion over a 30-min period. Serum samples were collected after 1, 4, 8, 24, 48 and 72 h, after 1 week, and after 1 month. To evaluate the efficacy of rasburicase, plasma and urinary concentrations of uric acid were determined by the standard method; the plasma activity of rasburicase was determined using a new assay developed by our laboratory (chromatography-mass method, a colorimetric 96-well microtiter plate assay). RESULTS: All the treated patients experienced a rapid reduction in their plasma uric acid concentration. Data showed an undetectable value within 1 h of treatment. The rasburicase effect ended after 50 h, with a slow increase in the plasma level of uric acid. CONCLUSION: A single dose of rasburicase is highly effective and well tolerated in the treatment of hyperuricemia in selected CKD patients.

Fibromuscular dysplasia of the renal arteries associated with antiphospholipid autoantibodies: two case reports.

A relationship appears to exist between antiphospholipid autoantibodies (APLA) and vascular occlusion, although the exact mechanism is still a matter of debate. We present and comment on two cases of renal artery occlusion in patients with concomitant presence of arterial fibromuscular dysplasia and high APLA titers.

Lymphocyte release of soluble IL-2 receptors in patients with minimal change nephropathy.

Minimal change nephrotic syndrome has been reported to be a lymphocyte-mediated disorder. It has been suggested that the secretion of lymphokine(s) is involved in the pathogenesis of MCN and in determining proteinuria. The presence of a soluble form of IL-2 receptor (sIL-2R) has been previously described in the sera of patients with some autoimmune disorders. In this work, we report the detection of high sIL-2R levels, both in the plasma (mean value 844 +/- 436 U/ml versus normal value 276 +/- 86 U/ml) and urine of patients with MCN during the nephrotic phase alone. Instead, when the patients achieve stable remission, sIL-2R levels decrease to within normal values (mean value 332 +/- 272 U/ml). Furthermore, during the nephrotic syndrome we observed a significant inverse relationship between sIL-2R plasma levels and the mitogenic response to PHA (p less than 0.005). Since sIL-2R exerts a down-modulation on T-proliferative expansion, sIL-2R might represent one of the inhibitory serum factors extensively reported in the serum of patients with MCN-induced nephrotic syndrome.

Do calcium channel blockers have any influence on the immunological status of renal graft recipients on ciclosporin therapy?

We have assessed the peripheral distribution of T cells, using the monoclonal antibodies OKT3, OKT4, OKT8 and LEU7 and the proliferative response to phytohaemagglutinin (PHA), in 10 renal transplant recipients. In each patient, the immunological pattern was evaluated twice, both before and after 1 month of calcium antagonist (calcium channel blockers, CaA) treatment. During treatment with CaA, we have observed both a significant decrease in the mitogenic response to PHA and a significant increase in OKT8 cells. Our data support the hypothesis that CaAs per se may have an immunomodulatory effect on T cell distribution independently of changes in ciclosporin (CS) blood levels. These results could also provide a cellular basis for synergism between CS and CaA.

The acid-base balance and the electroencephalographic pattern in patients on biofiltration treatment.

Electroencephalogram (EEG) monitoring and arterial blood gases was performed during biofiltration (BF) treatment and during conventional acetate hemodialysis (HDA). Biofiltration is an ultrashort hemodiafiltration with 3 liters of substitution fluid (Na+ 145 mEq/l, HCO-3 100 mEq/l). Our data show a better correction of acid-base balance during BF than during HDA. Moreover, we observe a lower incidence of EEG disturbancies on BF, that suggests a better neurological tolerance of this treatment.

Berger's nephropathy: relationship between histological pattern, blood pressure and renin.

Vascular damage (VD), glomerular sclerosis (GS), renin (PRA) and blood pressure were assessed in 50 patients with Berger's nephropathy. GS was present in 5/15 patients without VD and affected more than 15 per cent of glomeruli in seven patients with minimal VD. Nine out of 19 patients with GS were normotensive. VD was present in 35 patients: 16 were hypertensive and 19 normotensive. Therefore hypertension is not the only mechanism responsible for VD. In the seven normotensive patients with high PRA, GS was not present while VD was absent or minimal.

Cell mediated immunity in idiopathic glomerulonephritis.

Various recent reports have suggested the presence of a functional defect of lymphocyte subpopulations in minimal-change nephropathy during the active phase. A probable role of inhibitory humoral factor(s) has been hypothesized. However, other authors have been unable to detect a significant difference between plasma from patients with nephrotic syndrome due to minimal-change nephropathy and plasma from other glomerulonephritis in the degree of inhibition of mitogen-induced lymphocyte transformation. In our study, T cell function, as measured by the response to PHA in autologous plasma, was depressed only in patients with minimal-change nephrotic syndrome and in patients with membranoproliferative glomerulonephritis. The lymphocyte function returned to normal when lymphocytes were cultured in homologous plasma. The lymphocyte responsiveness of patients with other glomerulonephritis with or without nephrotic syndrome was normal in both autologous and homologous plasma. Moreover, only plasma from patients with minimal-change nephropathy in the active phase and with membranoproliferative glomerulonephritis were able to induce inhibition of mitogenesis of lymphocytes from healthy donors. These data seem to confirm the presence of specific humoral inhibitory factor(s) in the plasma of these patients. Finally, preliminary findings seem to demonstrate an increase of the number of TG cells in patients with minimal-change nephropathy in remission who relapse early in the subsequent follow-up.

Lymphocyte hyporesponsiveness during edema, proteinuria and hypertension (EPH) gestosis.

In vitro immunological tests showed that patients with pre-eclampsia are characterized by a greater degree of lymphocyte hyporesponsiveness to mitogens during pregnancy than normotensive controls. Thus, a relationship has been hypothesized between the hypoimmune lymphocyte response and the pathogenesis of the disease. We studied 20 non-pregnant healthy volunteers (group a), 11 women with a normal pregnancy (group b) and 13 women with EPH gestosis (group c). In all patients we determined the number of lymphocytes and the lymphocyte function (PHA, Con A, PWM responsiveness) in autologous and homologous plasma during pregnancy and 5 to 30 days after delivery. The mean values of the number of EAC and E rosettes in the three groups studied were similar. The mean values of the mitogenic response to PHA in autologous plasma were significantly reduced in both groups b and c in comparison with group a, but there was no statistical difference between groups b and c. The PHA lymphocyte responsiveness returned to normal in both homologous and autologous plasma after delivery. Our data demonstrate that no difference exists between pregnant women with and without pre-eclampsia as regards impaired cell-mediated lymphocyte response in vitro. Moreover, the diminished lymphocyte responsiveness to mitogens during pregnancy seems to be due to humoral circulating factor(s).