Lupus-like in vitro anticoagulant activity in end-stage renal disease

Lupus-like anticoagulant is diagnosed by a prolonged activated plasma thromboplastin time not corrected after incubation with normal plasma, prolongation of diluted tissue thromboplastin time and of diluted Russel's viper venom time, excluding factor deficiencies or specific coagulation inhibitors. We studied the presence of this 'lupus-like anticoagulant' in 100 patients with end-stage renal disease, 56 on hemodialysis and 44 on conservative treatment. 'Lupus-like anticoagulant' activity was found in vitro in the blood of 22 patients (22%) being a significantly higher prevalence than that found in 125 patients with systemic lupus erythematosus (15%) and in 50 healthy controls (0%). Hemodialysis patients showed 'lupus-like anticoagulant' activity in 30% cases, compared to 11% patients on conservative treatment. The presence of 'lupus-like anticoagulant' was unrelated with primary disease or medication received. The incidence of thrombosis in patients with this in vitro anticoagulant was higher than in patients without it (23 vs. 13%), although this difference is not significant. We conclude that prevalence of 'lupus-like anticoagulant' is high in patients with end-stage renal disease, a previously unreported observation. Its clinical and pathogenetic significance should be studied further.     

Global spending on orphan drugs in France, Germany, the UK, Italy and Spain during 2007

Background

Orphan drugs are indicated for the treatment of rare diseases which, in the EU, are defined as those with a prevalence of <5 per 10 000 inhabitants. Characteristically, these diseases negatively affect health-related quality of life and may be life threatening. The EU has passed legislation to encourage pharmaceutical companies to invest in research programmes into rare diseases, with the aim of developing new, safe and effective orphan drugs.

Objectives

To describe the status of orphan drugs in five countries in the EU (France, Germany, the UK, Italy and Spain), estimate the mean annual cost per patient and indication of these orphan drugs, and determine the associated cost of these drugs in comparison with overall spending on drugs in each country (year 2007 values).

Methods

The analysis was limited solely to costs of orphan drugs with sales data available for 2007. The mean annual cost per patient was estimated using recommended regimens for maintenance dose and duration from the summary of product characteristics. Likewise, the ratio between annual costs per patient for treatment of each disease and its prevalence was calculated. Sales data were available for at least one of the countries studied for 38 of the 44 orphan drugs authorized by the European Medicines Agency. Only 21 products had data available for all five countries studied.

Results

Germany was the country with access to the largest number of orphan drugs (36), followed by the UK (34), Spain (28), France (27) and Italy (25). The mean annual cost per patient and indication of the 38 orphan drugs on the market ranged widely from €331 to €337 501. It appears that orphan drugs indicated to treat diseases with a prevalence of <2 per 10 000 inhabitants have higher annual per-patient costs than those indicated to treat diseases with a higher prevalence. The percentage of total drug spending accounted for by orphan drugs in 2007 was 1.7% in France, 2.1% in Germany, 1.0% in the UK, 1.5% in Italy and 2.0% in Spain, with an average overall percentage of 1.7% for these five countries.

Conclusions

In 2007, spending on orphan drugs in five European countries was acceptable in terms of the percentage of these countries’ overall drug expenditure. Mean annual costs per patient of orphan drugs varied widely, with costs being related to the prevalence of the disease for which the product is indicated.     

Acute lymphoblastic leukemia in a child with constitutional ring chromosome 21

This report describes a case of acute lymphoblastic leukemia with non-B, non-T, common acute lymphocytic leukemia antigen-positive blasts in a 13-year-old child with constitutional ring chromosome #21. Because ring chromosome #21 is a rare chromosomal disorder, it is likely that the leukemia transformation is related to the chromosomal anomaly.     

The feature of Metabolic Syndrome in HIV naive patients is not the same of those treated: Results from a prospective study

Metabolic Syndrome (MS) is a common disorder combining obesity, dyslipidemia, hypertension, and insulin resistance. Its prevalence among HIV-infected people is still debated. Besides, how antiretroviral therapy and HIV infection per se are related to MS is still unclear. All treatment-naïve patients attending scheduled visits at CISAI group hospitals between January and December 2007 were eligible for the study. Patients without MS at enrolment were followed-up for 3 years or until they developed MS, diagnosed according to the National Cholesterol Education Program (NCEP) definition. The main objective was to assess the 3-years incidence of MS. MS was evaluated for 188 subjects. Out of them, 62 (33.0%) had started HAART at enrolment, whereas 67 (35.6%) more started during the observation. 59 (31.4%) were still treatment-naive at the study end. MS was newly diagnosed in 14 patients. The incidence was 2.60 cases/100 person-years (95% CI 1.47–4.51), 2.75 (1.11–5.72) among HAART-naïve patients and 2.65 (1.23–5.03) in subjects on HAART. Blood pressure did not change in the study period, whereas in naive patients the HDL level significantly lowered (median –6.0 vs. 4.0, P < 0.0001) compared to HAART-treated patients. Triglicerides increased significantly in HAART subjects (median 12.0 vs. 1.0, P = 0.02), as well as blood glucose (median 6.0 vs. 1.0, P = 0.01). In our population, the overall MS incidence was low and largely similar in patients who started HAART or remained naive. However, the feature of MS was different in the two groups, suggesting that in untreated and treated patients MS developed through different metabolic pathways.     

Direct assessment of splanchnic uptake and metabolic effects of human and porcine insulin

The hepatic vein catheterization technique was used to quantitate the splanchnic uptake and the metabolic effects of biosynthetic human insulin (BHI) and porcine insulin (PI) in normal man. BHI and PI were infused into a peripheral vein (0.9-1.3 mU kg-1 min-1) for 60 min together with SRIH (0.6 mg/h) to inhibit endogenous insulin secretion and glucose to induce moderate hyperglycemia (9-10 mmol/liter). During the infusion period, arterial-hepatic venous difference of plasma C-peptide as well as splanchnic C-peptide output fell by more than 98% indicating virtually complete cessation of endogenous insulin release. Under these conditions, the arterial-hepatic venous differences in plasma insulin concentrations represent a valid and direct measurement of splanchnic insulin uptake. During BHI infusion, arterial insulin levels rose to 82 +/- 11 (SE) microU/ml (range: 33-105 microU/ml). Splanchnic insulin uptake paralleled the rise of arterial insulin, reaching 430 +/- 72 microU kg-1 min-1 at 60 min. No appreciable difference between BHI and PI was demonstrable. A highly significant correlation between arterial insulin concentrations and splanchnic insulin uptake was found (r = 0.816; P less than 0.001). Accordingly, both fractional splanchnic insulin extraction and splanchnic insulin clearance remained unchanged throughout insulin infusion and averaged 70 +/- 4% and 5.3 +/- 2 ml kg-1 min-1, respectively. With BHI infusion, splanchnic glucose balance (-8.5 +/- 0.9 mumol kg-1 min-1, basal) became positive (7.3 +/- 1 mumol kg-1 min-1). In contrast, basal splanchnic lactate uptake was inhibited by BHI and there was lactate production (from 3.4 +/- 0.9 to -1.7 +/- 1.4 mumol kg-1 min-1). Similar changes in splanchnic glucose and lactate metabolism occurred during PI infusion. These studies indicate that: 1) A considerable amount of insulin (70 +/- 4%) is extracted by the splanchnic bed on a single passage, after exogenous administration of either human insulin or PI; 2) over a physiological range of insulin concentrations (33-105 microU/ml) a linear relationship exists between arterial insulin concentrations and splanchnic insulin removal; and 3) BHI and PI do not differ appreciably with respect to their uptake and metabolic effects at the splanchnic level.     

Incidence and prognosis of acute renal failure in older patients

Few studies have assessed the prevalence and outcome of acute renal failure (ARF) in the elderly. Among 437 ARF cases prospectively studied during a nine-year period in a nephrology department, 152 (35%) occurred in patients over 70 years of age (Group 1). Patients over 70 account for only 10.5% of all hospital admissions in our country, and prevalence of ARF was 3.5 times higher in these patients than in younger people. Acute tubular necrosis (ATN) was diagnosed in 40% of Group 1 and 52% of the younger patients (Group 2) (P less than .05), whereas prerenal ARF was found in 47% and 32%, respectively (P less than .001). Dehydration was the most frequent cause of prerenal ARF in the elderly (51%). The etiological distribution of ATN was similar in both groups, being of multifactorial origin in most cases. Oliguria was present in 49% of ATN in Group 1 and in 66% of Group 2 (P less than .05). There were no significant differences in dialysis needs. Mortality was higher in the elderly in all types of ARF, although differences did not reach statistical significance. Need for dialysis, mechanical respiration, decreased level of consciousness, and hypotension were associated with poor prognosis in both groups. Total recovery from ARF in older persons was less frequent and slower than in younger patients. It may be concluded that patients over 70 years of age are at high risk for developing ARF; nevertheless, age should not be used as a discriminating factor in therapeutic decisions concerning ARF.     

Acute cardiovascular effects of intravenous cyclosporine

The acute effects of intravenous (i.v.) cyclosporine A (CsA) on blood pressure and other haemodynamic parameters were examined in 8 patients with end-stage renal disease on haemodialysis (HD). The study was performed after the mid-week haemodialysis session, when the patients were on their dry body weight. Each patient received an i.v. infusion of 5 mg/kg of CsA in 120 ml of 5% dextrose in water during 2 hours. Heart rate, systolic and diastolic blood pressure (SBP, DBP) were monitored by the Holter system. An echocardiogram (M-mode 2-dimensional and Doppler sonography) was performed using an automatic device (Ultramark 6) before CsA administration, at 30, 60 and 120 minutes during CsA infusion, and at 30 minutes thereafter. SBP, DBP and calculated peripheral vascular resistance (CPVR) increased significantly in respect to basal values at 120 and 150 minutes (SBP: basal 130±21, 120 min: 136±20, 150 min: 140±18, p<0.05 and p<0.01, respectively. DBP: basal 80±9, 120 min: 86±13, 150 min: 88±13, p<0.05 and p<0.01, respectively. CPVR: basal 1000±228, 120 min: 1178±305, 150 min: 1236±270 dyne/s/cm⁵, p<0.01). However, systolic volume (SV) and cardiac output (CO) showed significant decreases from the basal values (SV: basal 103±29, 120 min: 85±22, 150 min: 85±17, p<0.05. CO: basal 8.2±2, 120 min: 7.3±1.1, 150 min: 7±1.2l/min, p<0.05). In conclusion, CsA infusion produces a significant elevation of blood pressure, which seems to be mediated by a direct action on peripheral vascular resistance.     

Membranous nephropathy: recurrence after kidney transplantation

BACKGROUND.: It is supposed that about 5% of dialysis patients had membranousnephropathy as a cause for their renal failure. Despite of thisprevalence, only 33 cases of recurrent membranous nephropathyafter kidney transplantation have been reported in the Englishliterature. METHODS.: Among 509 recipients of renal allografts, membranous glomerulonephritiswas the cause of renal failure in five patients, who receivedsix transplants. RESULTS.: Recurrence of the disease was observed in three allografts (50%)in three patients, all of them were on treatment with cyclosporinand low-dose prednisone. Proteinuria appeared at 2, 5 and 19months after grafting. One patient experienced a spontaneousremission after 12 months and he is free from proteinuria andwith good renal function after 5 years. The remaining two patientspresented progressive renal function deterioration and returnedto haemodialysis 24 and 17 months after the appearance of proteinuria.In these patients increasing the immunosuppression did not produceany beneficial effect. One of those patients underwent a secondtransplant; recurrence of the membranous nephropathy has notbeen observed after 3 years of follow-up. CONCLUSIONS.: In this study three new cases of recurrence of membranous nephropathyare reported. One patient experienced a spontaneous remissionof proteinuria. Recurrence of membranous nephropathy in renalallograft was very high in our series. Its appearance was associatedwith poor prognosis of the graft in most patients, althoughspontaneous remission of proteinuria is possible.