Excited States in Bilayer Graphene Quantum Dots.

We report ground- and excited-state transport through an electrostatically defined few-hole quantum dot in bilayer graphene in both parallel and perpendicular applied magnetic fields. A remarkably clear level scheme for the two-particle spectra is found by analyzing finite bias spectroscopy data within a two-particle model including spin and valley degrees of freedom. We identify the two-hole ground state to be a spin-triplet and valley-singlet state. This spin alignment can be seen as Hund's rule for a valley-degenerate system, which is fundamentally different from quantum dots in carbon nanotubes, where the two-particle ground state is a spin-singlet state. The spin-singlet excited states are found to be valley-triplet states by tilting the magnetic field with respect to the sample plane. We quantify the exchange energy to be 0.35 meV and measure a valley and spin g factor of 36 and 2, respectively.

Impact of sex and glucose-lowering treatments on hypoglycaemic symptoms in people with type 2 diabetes and chronic kidney disease. The French Chronic Kidney Disease - Renal Epidemiology and Information Network (CKD-REIN) Study.

AIM: To describe current practices of glucose-lowering treatments in people with diabetes and chronic kidney disease (CKD), the associated glucose control and hypoglycaemic symptoms, with an emphasis on sex differences. METHODS: Among the 3033 patients with CKD stages 3-5 recruited into the French CKD-REIN study, 645 men and 288 women had type 2 diabetes and were treated by glucose-lowering drugs. RESULTS: Overall, 31% were treated only with insulin, 28% with combinations of insulin and another drug, 42% with non-insulin glucose-lowering drugs. In CKD stage 3, 40% of patients used metformin, 12% at stages 4&5, similar for men and women; in CKD stage 3, 53% used insulin, similar for men and women, but at stages 4&5, 59% of men and 77% of women used insulin. Patients were reasonably well controlled, with a median HbA1c of 7.1% (54mmol/mol) in men, 7.4% (57mmol/mol) in women (P=0.0003). Hypoglycaemic symptoms were reported by 40% of men and 59% of women; they were not associated with the estimated glomerular filtration rate, nor with albuminuria or with HbA1c in multivariable analyses, but they were more frequent in people treated with insulin, particularly with fast-acting and pre-mixed insulins. CONCLUSION: Glucose-lowering treatment, HbA1c and hypoglycaemic symptoms were sex dependent. Metformin use was similar in men and women, but unexpectedly low in CKD stage 3; its use could be encouraged rather than resorting to insulin. Hypoglycaemic symptoms were frequent and need to be more closely monitored, with appropriate patient-education, especially in women.

Long-term effects of aldosterone blockade in resistant hypertension associated with chronic kidney disease.

Hypertension is a major risk factor for the development and progression of chronic kidney disease (CKD). Mineralocorticoid receptor antagonists (MRAs) are effective in the management of resistant hypertension but are not widely used in CKD because of the risk of hyperkalemia. We retrospectively evaluated the long-term effects and safety of MRAs added to a pre-existing antihypertensive regimen in subjects with resistant hypertension associated with stage 3 CKD. In all, 32 patients were treated with spironolactone and 4 with eplerenone for a median follow-up of 312 days. MRAs induced a significant decrease in systolic blood pressure from 162±22 to 138±14 mm Hg (P<0.0001) and in diastolic blood pressure from 87±17 to 74±12 mm Hg (P<0.0001). Serum potassium increased from 4.0±0.5 to 4.4±0.5 mEq l(-1) (P=0.0001), with the highest value being 5.8 mEq l(-1). The serum creatinine increased from 1.5±0.3 to 1.8±0.5 mg dl(-1) (P=0.0004) and the estimated glomerular filtration rate decreased from 48.6±8.7 to 41.2±11.5 ml min(-1) per 1.73 m(2) (P=0.0002). One case of acute renal failure and three cases of significant hyperkalemia occurred. MRAs significantly reduced blood pressure in subjects with resistant hypertension associated with stage 3 CKD, although close biochemical monitoring is recommended because of an increased risk of hyperkalemia and worsening of renal function.

[DOPPS estimate of patient life years attributable to modifiable hemodialysis practices in Spain]. / Estimación, según el estudio DOPPS, de los años de vida de pacientes atribuibles a las prácticas de hemodiálisis modificables en España.

The increased mortality risk in hemodialysis (HD) patients unable to meet six targets in different areas of HD practice has been reported previously. Using a prevalent cross-sectional sample of Spanish HD patients (n = 613) from the second stage of the Dialysis Outcomes and Practice Patterns Study to determine the percentage with low dialysis dose, hyperphosphatemia, hypercalcemia, hypoalbuminemia, anemia, and catheter use and based on the mortality hazard ratios and the total HD population in Spain, according to the Spanish Society of Nephrology Report, we estimated the number of patient life years that could potentially be gained in our country. These characteristics of HD practice were selected because each is modifiable through changes in practice, each is associated with mortality, and each has a large number of patients outside the target guidelines. The targets that define "within guidelines" are as follows: dialysis dose (single pool Kt/V >1.2), anemia (hemoglobin >110 g/L), albumin after standardization (>40 g/L), serum phosphorus (1.1-1.5 mmol/L), serum calcium (2.1-2.4 mmol/L), and facility catheter use (<10%). Cox proportional hazards regression models were used to calculate the relative risk of mortality for all patients outside each guideline. In all models, calcium values were adjusted for low serum albumin. A separate Cox survival model adjusted for all six HD practices simultaneously to account for correlation that may exist between some facility practices. All models were adjusted for age, sex, race, time on ESRD, and 14 summary comorbid conditions. Patient years attributable to each of the six practice patterns were estimated and are reported here as the potential patient years gained. Comparison of the estimates by individual guideline shows that, in Spain, increasing patient albumin above 40 g/L in all patients would lead to an estimated gain of 9,269 patient years (a 7.9% increase). Additionally, if all facilities could decrease catheter use to less than 10%, 2,842 patient years could be gained (a 2.4% increase). Though it may be an unrealistic goal, if all Spanish patients currently outside the guidelines achieved all six target levels, an estimated 17,300 life years could be gained over the next five years (a 15% increase). A more achievable goal of bringing 50% of patients who are currently outside targets within targets would result in 9,266 life years gained. In conclusion, this analysis suggests large opportunities to improve HD patient care in Spain.

Dopps estimate of patient life years attributable to modifiable haemodialysis practices in Belgium.

BACKGROUND: Various organizations have published clinical practice guidelines for the care of haemodialysis patients. However, it is unknown to what extent improving or even reaching perfect compliance with guidelines would improve the survival of HD patients in Belgium. METHODS: Using data from the second phase of the Dialysis Outcomes and Practice Patterns Study (DOPPS), the proportion of haemodialysis patients failing to meet six key practice targets (Kt/V > or = 1.2, haemoglobin > or =11 g/dl, phosphate 1.1-1.5 mmol/l, calcium 2.1-2, 4 mmol/l, albumin > or =40 g/l, and facility catheter use < or =10%) was calculated along with the relative risk of mortality associated with being outside these targets. The life years potentially gained from adherence to the six targets, both separately and all six together were then estimated. RESULTS: The percentage of patients outside the targets were as follows: 30.3%, Kt/V; 33.6%, haemoglobin; 56.2%, phosphate; 58.2%, calcium; 67.1%, albumin; and 91.1%, catheter. Estimated patient life years gained with improved compliance with guidelines was highest for albumin (3.670) and catheter use (2.331) but still substantial for the other four targets (ranging from 551 to 1.258). The total of patient years gained if 100% of patients have all six practices brought within target reaches 7.516 years. A conservative estimate of 50% of patients within all targets still yields an improvement of survival of 3.958 patient years. CONCLUSION: This analysis suggests large opportunities to improve HD patient care in Belgium. The avoidance of HD catheters, with the use of AV fistulas whenever possible, should be given a high priority. Admittedly, these calculations assume causality or partial causality that has not been definitively proven. Still, if causality is only partial, the results emphasize that the improvement of patient care through adherence to targets of clinical guidelines might be substantial and all Belgian nephrologists and staff members of dialysis units should carefully pursue every potential effort.

[DOPPS estimate of guideline impact on survival in hemodialysis in Italy]. / Stima DOPPS dell'impatto delle linee guida sulla sopravvivenza in emodialisi in Italia.

Knowing the relative risk (RR) of mortality associated with being outside the guideline targets and the percentage of patients in this situation, it is possible to estimate the number of patient life years that could be gained from adhering to guideline recommendations. We used a prevalent cross-sectional sample of 576 Italian patients from the Dialysis Outcomes and Practices Patterns Study (DOPPS) phase II (2002-2004) to determine the percentage of patients who failed to meet the Italian Society of Nephrology's targets for dialysis dose (spKt/V ≥ 1.3), anemia management (hemoglobin ≥ 11 g/dL), and mineral metabolism (serum calcium and phosphorus: ≤ 2.6 and ≤ 1.8 mmol/L, respectively), and the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) targets for nutritional status (serum albumin ≥ 4 g/dL) and vascular access (facility catheter use ≤ 10%). We used a larger random sample of DOPPS patients to establish the adjusted RRs of mortality associated with the 6 examined targets. The percentage of patients outside the targets and the adjusted RRs were 34% and 1.12 for dialysis dose, 37.7% and 1.20 for anemia management, 40.8% and 1.14 for phosphorus, 14.4% and 1.22 for calcium, 62.5% and 1.46 for albumin, and 40.1% and 1.20 for facility catheter use. The adjusted sum of life years potentially gained by complete adherence to all 6 guidelines was 25,156 over a period of 5 years (2006-2010); a more conservative estimate, modeling life years potentially gained by bringing half of all patients outside targets within them, was 13,382. In conclusion, this analysis suggests opportunities to improve hemodialysis patient care in Italy. The magnitude of potential savings in life years should encourage greater adherence to guidelines and practices that are significantly associated with better survival.

Symptoms of depression, prescription of benzodiazepines, and the risk of death in hemodialysis patients in Japan.

Many hemodialysis patients in Japan have symptoms of depression, but whether those patients are treated appropriately is unknown. As part of the Dialysis Outcomes and Practice Patterns Study, data on symptoms of depression, physician-diagnosed depression, prescribed medications, and death were collected prospectively in cohorts in Japan (n=1603) and 11 other countries (n=5872). Symptoms of depression were as prevalent in Japan as elsewhere, but in Japan a much smaller percentage of patients had physician-diagnosed depression: only 2% in Japan vs 17% elsewhere. Antidepressants were much less commonly prescribed in Japan: only 1% in Japan vs 17% elsewhere for patients with many and frequent symptoms of depression, and 16% in Japan vs 34% elsewhere for patients with physician-diagnosed depression. In Japan, symptoms of depression were associated with prescription of benzodiazepines (without antidepressants), and patients with physician-diagnosed depression were twice as likely to be given benzodiazepines: 32% in Japan vs 16% elsewhere. Benzodiazepine monotherapy was associated with death (relative risk 1.56, 95% confidence interval (CI), 1.25-1.94), even after adjustments for 13 likely confounders (relative risk 1.27, 95% CI, 1.01-1.59). Hemodialysis patients in Japan with symptoms of depression are given not antidepressants but benzodiazepines, a practice associated with higher mortality.

Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study.

The available data on bone fractures in hemodialysis (HD) patients are limited to results of a few studies of subgroups of patients in the United States. This study describes the prevalence of hip fractures and the incidence and risk factors associated with hip and other fractures in representative groups of HD facilities (n=320) and patients (n=12 782) from the 12 countries in the second phase of the Dialysis Outcomes and Practice Patterns Study (2002-2004). Among prevalent patients, 2.6% had a prior hip fracture. The incidence of fractures was 8.9 per 1000 patient years for new hip fractures and 25.6 per 1000 for any new fracture. Older age (relative risk (RR)(HIP)=1.91, RR(ANY)=1.33, P<0.0001), female sex (RR(HIP)=1.41, P=0.02; RR(ANY)=1.59, P<0.0001), prior kidney transplant (RR(HIP)=2.35, P=0.04; RR(ANY)=1.76, P=0.007), and low serum albumin (RR(HIP)=1.85, RR(ANY)=1.45, per 1 g/dl lower, P<0.0001) were predictive of new fractures. Elevated risk of new hip fracture was observed for selective serotonin reuptake inhibitors and combination narcotic medications (RR=1.63, RR=1.74, respectively, P<0.05). Several medications were associated with risk of any new fracture: narcotic pain medications (RR=1.67, P=0.02), benzodiazepines (RR=1.31, P=0.03), adrenal cortical steroids (RR=1.40, P<0.05), and combination narcotic medications (RR=1.72, P=0.001). Parathyroid hormone (PTH) levels >900 pg/ml were associated with an elevated risk of any new fracture (RR=1.72, P<0.05) versus PTH 150-300. The results suggest that greater selectivity in prescribing several classes of psychoactive drugs and more efficient treatment of secondary hyperparathyroidism may help reduce the burden of fractures in HD patients.

[The Dialysis Outcomes and Practice Patterns Study (DOPPS): results of the Italian cohort]. / Lo studio DOPPS (Dialysis Outcomes and Practice Patterns Study): risultati della coorte italiana.

BACKGROUND: The Dialysis Outcomes and Practice Patterns Study (DOPPS) is an international prospective, longitudinal, observational study examining the relationship between dialysis unit practices and outcomes for hemodialysis (HD) patients in seven developed countries France, Germany, Italy, Spain, United Kingdom, Japan and the United States. Results of the DOPPS in Italy are the subject of this report. METHODS: A national representative sample of 20 dialysis units (21 in Germany) was randomly selected in each of the European DOPPS countries (Euro-DOPPS). In these units, the HD in-center patients were included on a facility census, and their survival rates continuously monitored. A representative sample of incident (269 in Italy, 1553 in the Euro-DOPPS) and prevalent (600 in Italy, 3038 in the Euro-DOPPS) patients was randomly selected from the census for more detailed longitudinal investigation with regard to medical history, laboratory values and hospital admission. RESULTS: Comparing the Italian and Euro-DOPPS cohorts we found comparable mean age for prevalent patients (61.4 vs. 59.5 yrs), but incident patients were older in Italy. Italian prevalent patients had less cardiovascular disease, more satisfactory nutritional status and more frequent use of native vascular access. These data were associated with a comparable mortality (15.7 vs. 16.3 deaths/100 patient yrs), but morbidity was lower in Italy. Kt/V levels were comparable in the two cohorts (1.32 vs. 1.37), but 35% of Italian patients showed a Kt/V below the recommended target. Moreover, hemoglobin levels were below 11 g/dL in 60% of Italian patients. CONCLUSIONS: The DOPPS results bring to light several positive aspects and the opportunity for further possible improvements for Italian patients, but at the same time highlight some critical points that could represent a risk for dialysis quality.

Drug-induced thrombotic microangiopathy: incidence, prevention and management.

The term thrombotic microangiopathy (TMA) describes syndromes characterised by microangiopathic haemolytic anaemia, thrombocytopenia and variable signs of organ damage due to platelet thrombi in the microcirculation. In children, infections with Shigella dysenteriae type 1 or particular strains of Escherichia coli are the most common cause of TMA; in adults, a variety of underlying causes have been identified, such as bacterial and viral infections, bone marrow and organ transplantation, pregnancy, immune disorders and certain drugs. Although drug-induced TMA is a rare condition, it causes significant morbidity and mortality. Antineoplastic therapy may induce TMA. Most of the cases reported are associated with mitomycin. TMA has also been associated with cyclosporin, tacrolimus, muromonab-CD3 (OKT3) and other drugs such as interferon, anti-aggregating agents (ticlopidine, clopidogrel) and quinine. The early diagnosis of drug-induced TMA may be vital. Strict monitoring of renal function, urine and blood abnormalities, and arterial pressure has to be performed in patients undergoing therapy with potentially toxic drugs. The drug must be discontinued immediately in the case of suspected TMA. Treatment modalities sometimes effective in other forms of TMA have been used empirically. Although plasma exchange therapy seems to be of value, the effectiveness of this approach has yet to be proved in multicentre, randomised clinical studies.

Renoprotective therapy in patients with nondiabetic nephropathies.

End-stage renal failure (ESRF) represents a major health problem. Early diagnosis and effective measures to slow or to stop renal damage are essential goals for nephrologists to prevent or delay progression to ESRF. Identifying mechanisms of progressive parenchymal injury is instrumental in developing renoprotective strategies. Protein traffic through the glomerular barrier is an important determinant of progression in chronic nephropathies and proteinuria is the best predictor of renal outcome. At the moment, ACE inhibition is the most effective treatment in patients with chronic nondiabetic proteinuric nephropathies, reducing protein traffic, urinary protein excretion rate and progression to ESRF more effectively than conventional treatment. Low sodium diet and/or diuretic treatment may help to increase the antiproteinuric effect of ACE inhibitors by maximally activating the renin-angiotensin system. Intensified blood pressure control, whatever treatment is employed, also enhances the antiproteinuric response to ACE inhibitors. However, since this is not always sufficient to normalise urinary proteins and fully prevent renal damage, additional treatments may be needed in patients poorly or not responding to ACE inhibitors. These may include angiotensin II receptor antagonists, non-dihydropyridine calcium antagonists and perhaps low doses of nonsteroidal anti-inflammatory drugs. Preliminary data on multidrug treatments including these additional antiproteinuric agents are encouraging, but additional studies in larger patient numbers are needed to better define the risk/benefit profile of this innovative approach.

[Dialysis Outcomes and Practice Patterns Study: data on the use of central venous catheters in chronic hemodialysis]. / Dialysis Outcomes and Practice Patterns Study: données sur l'utilisation des cathéters veineux centraux en hémodialyse chronique.

Central venous catheters are widely used as vascular accesses for chronic haemodialysis. Different factors may lead to catheter use, whether clinical such as emergency dialysis, or related to practices specific to each dialysis unit or country. The Dialysis Outcomes and Practice Patterns Study is an observational study of more than 10,000 representative patients treated by haemodialysis followed over a two-year period in the United States, Japan, and in five European countries (France, Germany, Italy, Spain, United Kingdom). DOPPS data from the United States and Europe about catheters are reported in this paper. Catheter use is less frequent in Europe than in the US, both in incident and prevalent patients, and in patients who have been seen by a nephrologist in the pre-dialysis period. Tunneled and untunneled catheters are each associated with a significantly higher frequency of access infection compared to native arteriovenous fistulae and grafts. Patients with important comorbidities such as diabetes, cardiovascular diseases, malnutrition or dementia are more likely to be dialysed with tunneled catheters. Furthermore, patients initiating hemodialysis with a tunneled catheter display higher mortality risk compared to patients starting hemodialysis with a permanent access. In summary, DOPPS data indicate that central venous catheters are used for chronic haemodialysis in patients with a high level of morbidity, and that their utilisation is associated to an additional risk, particularly of infection, and to a lower survival for tunneled catheters. Appropriate care should limit the utilisation of central venous catheters to clinically undisputable indications.

Pretreatment blood pressure reliably predicts progression of chronic nephropathies. GISEN Group.

BACKGROUND: Random, nontimed blood pressure (BP) measurements in the outpatient clinic may fail to provide reliable information on actual daily BP control in renal patients on chronic antihypertensive therapy. METHODS: In a cohort of 163 patients with proteinuric chronic nephropathies followed prospectively with repeated BP and glomerular filtration rate (GFR) measurements, we compared baseline and follow-up pretreatment, morning ("trough," measured by standard procedures, and "0 minutes," measured by an automatic device) and post-treatment (120 minutes) measurements, with BP monitored up to 600 minutes after treatment administration. We then evaluated which BP value most reliably predicted GFR decline (delta GFR) and progression to end-stage renal failure (ESRF) over a median (interquartile range) follow-up of 20 (9 to 25) months. RESULTS: GFR decline was more reliably predicted by systolic as compared with diastolic BP and by pretreatment as compared to post-treatment BP, regardless of the timing and method of measurement, respectively. In particular, at the 120-minute baseline and follow-up measurements, systolic BP had no predictive value in patients with less severe renal insufficiency and baseline diastolic BP, regardless of the level of renal dysfunction. The BP predictive value was remarkably higher in ramipril than in conventionally treated patients. All follow-up-but no baseline-measurements reliably predicted the risk of ESRF in the entire study group. CONCLUSIONS: In patients with progressive chronic nephropathies, systolic BP and pretreatment morning BP measurements are the most reliable predictors of disease outcome and may serve to guide antihypertensive therapy in routine clinical activities and in prospective controlled trials, particularly in patients on angiotensin-converting enzyme inhibitor therapy. Reliability and relevance of single measurements taken at different times after treatment administration are questionable.

How much must blood pressure be reduced in order to obtain the remission of chronic renal disease?

Most chronic nephropathies are characterized by a progressive decline in glomerular filtration rate (GFR) that may lead to renal function replacement by dialysis or transplant. Hypertension has an extremely important role among the various mechanisms contributing to renal function deterioration. High blood pressure levels are associated with increased urinary excretion of proteins and the decrease of systemic and glomerular hypertension reduces urinary excretion of proteins and preserves renal function deterioration. Moreover, recent studies found that an intensified blood pressure control (less than 130/80 mmHg) can slow the progression of diabetic and non diabetic renal disease even more than conventional blood pressure control. The Ramipril Efficacy in Nephropathy (REIN) Study showed that ramipril, an ACE-inhibitor, slowed the rate of GFR decline and halved the combined risk of doubling serum creatinine or end stage renal failure (ESRF) in patients with nephrotic range proteinuria as compared to conventional antihypertensive therapy, at comparable levels of blood pressure control. In these patients, prolonged enough treatment (at least 36 months) with ramipril, lowered the velocity of GFR decline and reduced the risk of dialysis. Thus, both tight blood pressure control and ACE-inhibitors may have a renoprotective effect. It will be interesting to evaluate whether the two combined approaches may have sinergistic effects.

Thrombotic microangiopathy.

The term 'thrombotic microangiopathy' (TMA) describes syndromes of microangiopathic hemolytic anemia, thrombocytopenia, and variable signs of organ impairment, due to platelet aggregation in the microcirculation. The term 'hemolytic uremic syndrome' (HUS) has entered clinical use to describe childhood cases of TMA dominated by renal impairment, while the term 'thrombotic thrombocytopenic purpura' (TTP) refers to adult cases of TMA with predominant neurological abnormalities. HUS and TTP show the same histological lesion characterized by widening of the subendothelial space and microvascular thrombosis and their different manifestations are secondary to the different distribution of the microvascular lesions. Available evidence orients towards endothelial injury as an important factor in the sequence of events leading to the microangiopathic process. Here we provide an overview of the pathophysiology, epidemiology, clinical manifestations, and management of TMA.

Cimetidine transport in brush-border membrane vesicles from rat small intestine.

In previous studies, sulfoxide metabolite was observed in animal and human intestinal perfusions of cimetidine and other H2-antagonists. A sequence of follow-up studies is ongoing to assess the intestinal contributions of drug metabolism and drug and metabolite transport to variable drug absorption. An evaluation of these contributions to absorption variability is carried out in isolated fractions of the absorptive cells to uncouple the processes involved. In this report, data is presented on the drug entry step from a study on [3H]cimetidine uptake into isolated brush-border membrane vesicles from rat small intestine. A saturable component for cimetidine uptake was characterized with a Vmax and Km (mean +/- S.E.M.) of 6.1 +/- 1.5 nmol/30s/mg protein and 8.4 +/- 2.0 mM, respectively. Initial binding, and possibly intravesicular uptake, was inhibited by other cationic compounds including ranitidine, procainamide, imipramine, erythromycin, and cysteamine but not by TEA or by the organic anion, probenecid. Initial uptake was not inhibited by amino acids methionine, cysteine, or histidine, by the metabolite cimetidine sulfoxide, or by inhibitors of cimetidine sulfoxidation, methimazole, and diisothiocyanostilbene-2,2'-disulfonic acid. Equilibrium uptake was inhibited by ranitidine, procainamide, and cysteamine but not by erythromycin or imipramine. Initial cimetidine uptake was stimulated by an outwardly directed H+ gradient, and efflux was enhanced by an inwardly directed H+ gradient. Collapse of the H+ gradient as well as voltage-clamping potential difference to zero significantly reduced initial cimetidine uptake. The data is supportive of both a cimetidine/H+ exchange mechanism and a driving-force contribution from an inside negative proton or cation diffusion potential.

How to convert from traditional cyclosporine to the microemulsion formulation in stable renal transplant patients?

How to convert from traditional cyclosporine (CsA) to the microemulsion formulation in stable renal transplant patients is still a matter of debate. The present study was designed to evaluate the effects of changeover from traditional Sandimmune to Neoral formulation at two dose-ratio conversions on CsA pharmacokinetics, safety and tolerability particularly in terms of renal function. Thirty outpatients regularly followed at our Clinical Research Center were randomized to 1:1 or 1:0.75 dose-ratio conversion and assigned to the two groups according to a comparable renal function and time post-transplant. Patients underwent CsA pharmacokinetic evaluation and renal function measurements (GFR and RPF) before, at day 15, and at month 6 after conversion to Neoral formulation. More consistent CsA concentration-time profiles with Neoral than traditional formulation were obtained at the two time points of evaluation after conversion. At 1:1 dose-ratio conversion an increased absorption rate, reflected by a shorter time to maximum blood CsA concentration (Tmax), and a greater bioavailability, as shown by an increase in the peak CsA concentration (Cmax) and the 12-h exposure to drug defined by the area under the time-concentration curve (AUC0-->12 h) was found 15 d and 6 months after conversion to Neoral formulation. A similar AUC as compared with traditional Sandimmune was observed in those patients randomized to receive a 25% lower dose of Neoral formulation. All of patients defined as 'low' absorbers became 'high' absorbers as early as 15 d after conversion to Neoral formulation at 1:1 or 0.75 dose-ratio regimen. Overall mean GFR was unchanged in both conversion regimens during the 6 months of follow-up. However, there was a tendency to lower GFR even in some patients randomized to 1:0.75 conversion but mostly in those with 1:1 conversion. A limited sampling strategy utilizing three blood samples (0, 1, 3 h post-dosing of Neoral formulation) provided an excellent correlation with actual drug exposure (r = 0.977). Enhanced CsA absorption with the microemulsion formulation results in increased drug exposure that may reduce GFR in some patients who undergo 1:1 dose-ratio conversion. The Neoral formulation that permits a more effective, consistent, and predictable absorption of CsA may represent a great advantage in order to prevent acute and possibly chronic rejections. Efforts have to be made to find optimal therapeutic range and dosing schedule for this new formulation, which may be facilitated by using the limited sampling approach to predict AUC after only three-point sampling.

Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. "Gruppo Italiano di Studi Epidemiologici in Nefrologia" (GISEN).

We investigated the predictors of the rate of glomerular filtration rate decline (delta GFR) and progression to end-stage renal failure (ESRF) in the 352 patients with proteinuric non-diabetic chronic nephropathies [urinary protein excretion rate (UProt) > or = 1 g/24 hr, creatinine clearance 20 to 70 ml/min/1.73 m2] enrolled in the Ramipril Efficacy In Nephropathy (REIN) study. Overall the GFR declined linearly by 0.46 +/- 0.05 ml/min/1.73 m2/month (mean rate +/- SEM) over a median follow-up of 23 months (range 3 to 64 months), and progression to ESRF was 17.3%. Using multivariate analysis, higher UProt and mean arterial pressure (MAP) independently correlated with a faster delta GFR (P = 0.0001 and P = 0.0002, respectively) and progression to ESRF (P = 0.0001 and P = 0.003, respectively). Mean UProt and systolic blood pressure during follow-up were the only time-dependent covariates that significantly correlated with delta GFR (P = 0.005 and P = 0.003, respectively) and ESRF (P = 0.006 and P = 0.0001, respectively). After stratification for baseline UProt, patients in the lowest tertile (UProt < 1.9 g/24 hr) had the slowest delta GFR (0.16 +/- 0.07 ml/min/1.73 m2/month) and progression to ESRF (4.3%) as compared with patients in the middle tertile (UProt 2.0 to 3.8 g/24hr; delta GFR, 0.55 +/- 0.09 ml/min/1.73 m2/month, P = 0.0002; ESRF, 15.3%, P = 0.0001) and in the highest tertile (UProt 3.9 to 18.8 g/24 hr; delta GFR, 0.70 +/- 0.11 ml/min/1.73 m2/month, P = 0.0001; ESRF, 32.5%, P = 0.0001). Both delta GFR (P = 0.01) and progression to ESRF (P = 0.01) significantly differed even between the middle and the highest tertiles. On the contrary, stratification in tertiles of baseline MAP failed to segregate subgroups of patients into different risk levels. Patients with the highest proteinuria and blood pressure were those with the fastest progression (delta GFR, 0.91 +/- 0.23; ESRF 34.7%). Of interest, at each level of baseline MAP, a higher proteinuria was associated with a faster delta GFR and progression to ESRF. On the other hand, at each level of proteinuria, a faster delta GFR was associated with MAP only in the highest tertile (> 112 mm Hg) and the risk of ESRF was independent of the MAP. Thus, in chronic nephropathies proteinuria is the best independent predictor of both disease progression and ESRF. Arterial hypertension may contribute to the acceleration of renal injury associated with enhanced traffic of plasma proteins. Antihypertensive drugs that most effectively limit protein traffic at comparable levels of blood pressure are those that most effectively slow disease progression and delay or prevent ESRF in proteinuric chronic nephropathies.

Proteinuria predicts end-stage renal failure in non-diabetic chronic nephropathies. The "Gruppo Italiano di Studi Epidemiologici in Nefrologia" (GISEN).

We correlated baseline parameters with glomerular filtration rate (GFR) decline and kidney survival in 274 patients with proteinuric non-diabetic chronic nephropathies (creatinine clearance 20 to 70 ml/min/1.73 m2 and proteinuria > 1 g/24 hr over the last three months) enrolled in the Ramipril Efficacy In Nephropathy (REIN) trial. The GFR, evaluated at baseline, one, three and six months after randomization then every six months, declined linearly by 0.52 +/- 0.83 ml/min/1.73 m2/month (mean +/- SD) over a follow-up (median: range) of 21:3 to 52 months, and kidney survival was 64%. In multivariate analysis, higher baseline proteinuria (P = 0.006), and lower GFR (P = 0.0001) and creatinine clearance (P = 0.0001) correlated with a faster GFR decline. Higher proteinuria was the only baseline predictor of a shorter kidney survival (P = 0.0007) and its predictive value was independent of the underlying renal disease, treatment randomization, and blood pressure control during the followup. Patients in the lowest tertile of baseline proteinuria (< 2.5 g/24 hr) had the slowest rate of GFR decline (-0.25 +/- 0.72 ml/min/1.73 m2/month) and the highest kidney survival (94%), compared with patients in the middle tertile (proteinuria 2.5 to 4.3 g/24 hr; delta GFR, -0.59 +/- 0.82 ml/min/1.73 m2/month, P = 0.008; kidney survival 57%, P = 0.0011) and in the highest tertile (proteinuria > 4.3 g/24 hr; delta GFR, -0.79 +/- 0.87 ml/min/1.73 m2/month, P = 0.0001, kidney survival 44%, P = 0.0001). Kidney survival significantly differed even between the middle and highest tertiles (P < 0.05). Thus, in non-diabetic chronic nephropathies proteinuria is an independent and accurate predictor of disease progression and ESRF.