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The incentives provided by Orphan Drugs Regulations have promoted the development of drugs that effectively ameliorate the course of serious conditions that had previously been neglected. However, the treatment of each individual patient with any of these drugs - the so-called 'orphan drugs' - is so expensive, that the total burden for publicly funded Health care Service is enormous and may become unsustainable. Italy is no exception, if it is to abide by its basic tenet of providing access to essential medicines - free of charge - to the entire population. We do not see any glimpses of improvement on the horizon: therefore we suggest that radical change must be introduced. First, price negotiation ought to take place at the European level, not at the member state level. Second, pricing should take into account not only value for patients, but also costs of research and development (RD) plus production. Italian Medicines Agency (AIFA) should also support research focused on optimizing the effective use of orphan drugs in clinical practice. The challenges are complex: but AIFA is recognized as an authoritative body, and may be able to coagulate the agreement of other regulatory agencies for the ultimate purpose of achieving, for each of the orphan drugs a more reasonable 'European price'.

The aim of this study was to determine the economic burden from a societal perspective and health-related quality of life (HRQOL) of patients with Prader-Willi syndrome (PWS) in Europe. We conducted a cross-sectional study of patients with PWS from Spain, Bulgaria, Hungary, Germany, Italy, the UK, Sweden and France. Data on demographic characteristics, healthcare resource utilisation, informal care, labour productivity losses and HRQOL were collected from questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire. A total of 261 patients completed the questionnaire. The average annual costs ranged from € 3937 to € 67,484 between countries; the reference year for unit prices was 2012. Direct healthcare costs ranged from € 311 to € 18,760, direct non-healthcare costs ranged from € 1269 to € 44,035, and loss of labour productivity ranged from € 0 to € 2255. Costs were also shown to differ between children and adults. The mean EQ-5D index score for adult PWS patients ranged between 0.40 and 0.81 and the mean EQ-5D visual analogue scale score ranged between 51.25 and 90.00. The main strengths of this study lie in our bottom-up approach to costing and in the evaluation of PWS patients from a broad societal perspective. This type of analysis is very scarce in the international literature on rare diseases in comparison with other illnesses. We conclude that PWS patients incur considerable societal costs and experience substantial deterioration in HRQOL.

The aim of this study was to determine the economic burden from a societal perspective and the health-related quality of life (HRQOL) of patients with juvenile idiopathic arthritis (JIA) in Europe. We conducted a cross-sectional study of patients with JIA from Germany, Italy, Spain, France, the United Kingdom, Bulgaria, and Sweden. Data on demographic characteristics, healthcare resource utilization, informal care, labor productivity losses, and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D-5L) questionnaire. A total of 162 patients (67 Germany, 34 Sweden, 33 Italy, 23 United Kingdom, 4 France, and 1 Bulgaria) completed the questionnaire. Excluding Bulgarian results, due to small sample size, country-specific annual health care costs ranged from €18,913 to €36,396 (reference year: 2012). Estimated direct healthcare costs ranged from €11,068 to €22,138; direct non-healthcare costs ranged from €7837 to €14,155 and labor productivity losses ranged from €0 to €8715. Costs are also shown to differ between children and adults. The mean EQ-5D index score for JIA patients was estimated at between 0.44 and 0.88, and the mean EQ-5D visual analogue scale score was estimated at between 62 and 79. JIA patients incur considerable societal costs and experience substantial deterioration in HRQOL in some countries. Compared with previous studies, our results show a remarkable increase in annual healthcare costs for JIA patients. Reasons for the increase are the inclusion of non-professional caregiver costs, a wider use of biologics, and longer hospital stays.

To estimate the social/economic costs of fragile X syndrome (FXS) in Europe and to assess the health-related quality of life (HRQOL) of patients and caregivers. A cross-sectional study was conducted in a sample of European countries. Patients were recruited through patients’ associations. Data on their resource use and absence from the labour market were retrospectively obtained from an online questionnaire. Costs were estimated by a bottom-up approach and the EuroQol-5 Domain (EQ-5D) questionnaire was used to measure patients’ and caregivers’ HRQOL. Five countries were included in the analysis. The mean annual cost of FXS per patient varied from €4951 in Hungary to €58,862 in Sweden. Direct non-healthcare costs represented the majority of costs in all countries but there were differences in the share incurred by formal and informal care among those costs. Costs were also shown to differ between children and adults. Mean EQ-5D utility score for adult patients varied from 0.52 in France (n = 42) to 0.73 in Hungary (n = 2), while for caregivers this score was consistently inferior to 0.87. Our findings underline that, although its prevalence is low, FXS is costly from a societal perspective. They support the development of tailored policies to reduce the consequences of FXS on both patients and their relatives.

The aim of this study was to determine the economic burden from a societal perspective and the health-related quality of life (HRQOL) of patients with systemic sclerosis (SSc; scleroderma) in Europe. We conducted a cross-sectional study of patients with SSc (involving both localised and systemic sclerosis) from Germany, Italy, Spain, France, the UK, Hungary and Sweden. Data on demographic characteristics, healthcare resource utilisation, informal care, labour productivity losses and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire. A total of 589 patients completed the questionnaire. The rate of patients with localised scleroderma, limited cutan and diffuse cutan SSc were 28, 68 and 4 %, respectively. Average annual costs varied from country to country and ranged from € 4607 to € 30,797 (reference year: 2012). Estimated direct healthcare costs ranged from € 1413 to € 17,300; direct non-healthcare costs ranged from € 1875 to € 4684 and labour productivity losses ranged from € 1701 to € 14,444. The mean EQ-5D index score for adult SSc patients varied from 0.49 to 0.75 and the mean EQ-5D visual analogue scale score was between 58.72 and 65.86. The main strengths of this study lie in our bottom-up approach to costing and our evaluation of SSs patients from a broad societal perspective. This type of analysis is very unusual in the international literature on rare diseases in comparison with other illnesses. We concluded that SSc patients incur considerable societal costs and experience substantial deterioration in HRQOL.

Introduction: Membranous nephropathy (MN) is a rare, antibody-mediated glomerular disease that causes nephrotic syndrome in adults. It is a chronic disease with spontaneous remissions in approximately 30% of patients. The reminder, however, experience long periods of nephrotic syndrome and progress toward end-stage renal diseases. The ideal treatment for patients with MN is still matter of debate.Areas covered: The PubMed database was searched for original articles and reviews published up to August 2015. The search terms were: ‘membranous nephropathy’, ‘prognosis’, ‘pathogenesis’, and ‘treatment’.Expert opinion: Steroids in association with alkylating agents and calcineurin inhibitors are currently used and recommended by international guidelines as treatment of choice in MN. However the treatment benefits are uncertain, and often offset by adverse events. Evidence that B-cell function plays a role in the pathophysiology of this condition has suggested that rituximab, a monoclonal antibody that b...

Acute kidney injury (AKI) is imposing a severe burden of morbidity and mortality both in developed and developing countries. Also AKI has a major economic impact on healthcare expenditure. This is particularly so in poor countries where AKI especially impacts young productive people, imposing severe penury upon their families. The mission is to lessen the high burden in terms of death consequent to this disorder in low-resource regions, which in many cases is preventable and treatable with simple measures. The International Society of Nephrology has launched a long-term program, called "0 by 25", which advocates that zero people should die of untreated AKI in the poorest part of Africa, Asia, and Latin America by 2025. This paper illustrates how the project will be developed.

Treatment of systemic lupus erythematosus (SLE) with severe diffuse proliferative nephritis is often challenging, particularly in small children in whom a genetic conditioning is likely to play a role. The effectiveness of standard therapy based on glucocorticoid and immunosuppressive drugs is often unsatisfactory.A 4 year-old girl, whose parents were first-grade cousins of Moroccan ancestry, developed SLE that progressed to severe renal involvement despite standard therapy. She had persistently undetectable serum C4 levels and very low C3 levels (30 mg/dl), and extremely high anti-DNA titers (1:640) that remained unmodified during 2 years of follow-up. No mutations of genes encoding for complement inhibitors were detected. Despite aggressive therapy based on prednisone, plasma exchanges, and cyclosporine, the child worsened and eventually developed features of atypical hemolytic uremic syndrome (aHUS). Treatment with eculizumab provided prompt remission of vasculitis, proteinuria, and hematuria, with normalization of renal function. Two attempts to withdraw eculizumab were followed by severe relapses and rescued by reinstating treatment. The child has been treated with eculizumab for17 months without relevant side effects.C5 inhibition by eculizumab completely reversed clinical symptoms and laboratory renal signs of severe lupus nephritis. Blocking complement-system activation with the use of targeted drugs may be a new and exciting strategy to treat SLE patients unresponsive to conventional therapy.

The efficacy and safety of immunosuppression for idiopathic membranous nephropathy (IMN) with nephrotic syndrome are still controversial. A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed.The Cochrane Library, PUBMED, EMBASE, Chinese Database, and Clinical Trial Registries (June 2012) were searched to identify RCTs investigating the effect of immunosuppression on adults with IMN and nephrotic syndrome.This review was an update (36 RCTs, 1762 participants) of the 2004 version (18 RCTs, 1025 participants). Immunosuppression significantly reduced all-cause mortality or ESRD (15 RCTs, 791 participants; risk ratio, 0.58 [95% confidence interval, 0.36-0.95]; P=0.03). However, the result was not consistent when prespecified subgroup analyses were undertaken. Immunosuppression increased complete or partial remission (CR + PR) (16 RCTs, 864 participants; 1.31 [1.01-1.70]; P=0.04) but resulted in more withdrawals or hospitalizations (16 RCTs, 880 participants; 5.35 [2.19-13.02]; P=0.002). Corticosteroids combined with alkylating agents significantly reduced all-cause mortality or ESRD (8 RCTs, 448 participants; 0.44 [0.26-0.75]; P=0.002) and increased CR + PR (7 RCTs, 422 participants; 1.46 [1.13-1.89]; P=0.004) but led to more adverse events (4 RCTs, 303 participants; 4.20 [1.15-15.32]; P=0.03). Cyclophosphamide was safer than chlorambucil (3 RCTs, 147 participants; 0.48 [0.26-0.90]; P=0.02). Cyclosporine and mycophenolate mofetil failed to show superiority over alkylating agents. Tacrolimus and adrenocorticotropic hormone significantly reduced proteinuria.Alkylating agents plus corticosteroids had long-term and short-term benefits for adult IMN, but resulted in more withdrawals or hospitalizations.

Dabrafenib and trametinib, BRAF and MEK inhibitors, respectively, are effective targeted metastatic melanoma therapies, but little is known about their nephrotoxicity. Although tubulointerstitial injury has been the most widely reported renal side effect of targeted melanoma therapy, nephrotic syndrome has not been reported before. We report on a patient with metastatic melanoma who developed nephrotic syndrome during dabrafenib and trametinib treatment. Kidney biopsy showed diffuse loss of podocyte cytoarchitecture, extensive foot-process effacement, and glomerular endothelial injury. Kidney function and glomerular ultrastructural changes recovered fully after drug withdrawal. In vitro, BRAF inhibition decreased PLCe1 expression in podocytes, accompanied by a reduction in nephrin expression and an increase in permeability to albumin. Additionally, these drugs inhibited the podocyte–vascular endothelial growth factor (VEGF) system. In addition to implications for nephrotic syndrome pathophysiology, we suggest that patients given dabrafenib and trametinib be monitored closely for potential glomerular damage.

To review the results of the current therapy of lupus nephritis, highlighting successes and pitfalls, and summarizing the evidence available on the new agentsThe established treatment of lupus nephritis with aggressive immunosuppression, based on cyclophosphamide and steroids, has improved the outcome of lupus nephritis, but is burdened with significant adverse effects. The search for alternative, less toxic, therapeutic strategies has prompted a number of clinical studies, mycophenolate mofetil being the agent most studied. Results of trials showed that this drug is equally effective with fewer toxic complications than standard therapy, but its long-term efficacy is not yet known. During the last few years experimental studies in the pathogenesis of lupus nephritis have provided an enormous improvement in our knowledge and have offered the possibility to attempt targeting the disease with a more selective approach. The evidence for the role of these new therapies is reviewed.While the current alternative to standard therapy, i.e. mycophenolate mofetil, still needs to be confirmed with well designed, properly powered studies, new therapeutic agents, targeted to the pathogenetic mechanism of the disease, are promising improved efficacy with less toxicity.

The aim of this study was to determine the economic burden from a societal perspective and the health-related quality of life (HRQOL) of patients with histiocytosis in Europe. We conducted a cross-sectional study of patients with histiocytosis from France, Germany, Italy, Spain, Bulgaria, the UK, and Sweden. Data on demographic characteristics, health resource utilisation, informal care, loss of labour productivity and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire. A total of 134 patients (35 France, 32 Germany, 30 Italy, 24 Spain, 7 Bulgaria, 4 UK and 2 Sweden) completed the questionnaire. The average annual costs ranged from € 6832 to € 33,283 between countries, the year of reference being 2012. Estimated direct healthcare costs ranged from € 1698 to € 18,213; direct nonhealthcare costs ranged from € 2936 to € 17,622 and labour productivity losses ranged from € 1 to € 8855. The mean EQ-5D score for adult histiocytosis patients was estimated at between 0.32 and 0.85, and the mean EQ-5D visual analogue scale score was estimated at between 50.00 and 66.50. The main strengths of this study lie in our bottom-up approach to costing and in the evaluation of histiocytosis patients from a broad perspective (societal costs). This type of analysis is very scarce in international literature for rare diseases in comparison with other illnesses. We conclude that histiocytosis patients incur considerable societal costs and experience substantial deterioration in HRQOL.

Our goal was to provide data on the economic burden and health-related quality of life (HRQOL) of patients with cystic fibrosis (CF) and their caregivers in Europe.A cross-sectional study was carried out on adults and children with CF in eight European countries. Patients completed an anonymous questionnaire regarding their socio-demographic characteristics, use of healthcare services and presence of a caregiver. Costs were calculated with a bottom-up approach using unit costs from each participating country, and HRQOL was assessed using EQ-5D. The principal caregiver also answered a questionnaire on their characteristics, HRQOL and burden.A total of 905 patients with CF was included (399 adults and 506 children). The total average annual cost per patient varied from €21,144 in Bulgaria to €53,256 in Germany. Adults had higher direct healthcare costs than children, but children had much higher informal care costs (P 0.0001). Total costs increased with patients' level of dependence. In adults, mean utility fell between 0.640 and 0.870, and the visual analogue scale ranged from 46.0 to 69.7. There was no difference in caregiver HRQOL regardless of whether they cared for an adult or a child. However, caregivers who looked after a child had a significantly higher burden (P = 0.0013).Our study highlights the burden of CF in terms of costs and decreased HRQOL for both patients and their caregivers throughout Europe.

To assess the health-related quality of life (HRQOL) of patients with mucopolysaccharidosis (MPS) and their caregivers and to quantify the disease-related costs from a societal perspective. In the context of a multi-country study of rare diseases (BURQOL-RD project), a cross-sectional survey was performed among MPS patients in seven European countries. Data on demographic characteristics, health resource utilization, informal care, and loss of labor productivity were collected. The EQ-5D, Barthel index (BI), and Zarit burden interview (ZBI) questionnaires were used to assess patients’ and their informal caregivers’ quality of life, patients’ functional ability, and caregivers’ burden, respectively. Altogether, 120 patients (children 62 %, females 40 %) and 66 caregivers completed the questionnaire. Patients’ mean age was 16.5 years and median age at diagnosis was 3 years. Adult patients’ average EQ-5D and EQ VAS scores varied across countries from 0.13 to 0.43 and 30.0 to 62.2, respectively, mean BI was 46.7, and ZBI was 32.7. Mean informal care time was 51.3 h/week. The mean total annual cost per patient (reference year 2012) was €24,520 in Hungary, €25,993 in France, €84,921 in Italy, €94,384 in Spain, and €209,420 in Germany. Costs are also shown to differ between children and adults. Direct costs accounted for most of the costs in all five countries (80, 100, 99, 98, and 93 %, respectively). MPS patients experience substantial loss of HRQOL and their families take a remarkable part in their care. Although utilization of health and social care resources varies significantly across countries, MPS incurs considerable societal costs in all the countries studied.

Development of strategies for the early detection and prevention of non-communicable diseases, including kidney disease, is the only realistic strategy to avert an imminent global health and economic crisis and enhance equity in health care worldwide. In this article, we briefly examine the burden of non-communicable diseases, including diabetes, hypertension, cardiovascular disease and how chronic kidney disease (CKD) represents a key integrated element in the setting, even in developing countries. A possible explanation of the increasing number of people who have or are at risk to develop CKD in poor countries is also given. A survey of major screening and intervention programmes performed or ongoing globally is then presented, highlighting differences and hurdles of projects planned in developed or developing nations as well as in unprivileged communities in developed countries. Finally, some recommendations on future steps to implement prevention programmes in emerging worlds are provided.

Chronic renal diseases as a public health problem: Epidemiology, social, and economic implications. The impact of chronic kidney disease (CKD) on the global burden of diseases is probably underestimated by current methods of evaluation. However, CKD are emerging as a major health problem. First, the costs of renal replacement therapy are excedingly high and are consuming a significant proportion of health care budgets of developed countries, while in developing countries are out of reach. Second, complex interaction are clearly emerging between chronic kidney, cardiovascular disease, and diabetes.

Prevention of progression and remission/regression strategies for chronic renal diseases: Can we do better now than five years ago? The prevalence of chronic renal diseases is increasing worldwide. There is a great need to identify therapies that arrest disease progression to end-stage renal failure. Inhibition of renin-angiotensin system both by ACE inhibitors and angiotensin II receptor antagonists is probably the best therapeutic option available. Several large, multicenter studies have indeed shown a significant reduction in the risk of doubling baseline serum creatinine or progression toward end-stage renal failure in diabetic and nondiabetic patients with chronic nephropathies treated with ACE inhibitors or angiotensin II receptor antagonists. However, the number of patients that reach end-stage renal failure is still considerably high. Significant reduction of the incidence of end-stage renal disease is likely to be achieved in the next future for chronic nephropathies, provided that we can improve the degree of renoprotection. This goal may be attainable with a more complex strategy than with a single or dual pharmacologic intervention on the renin-angiotensin system. Strict control of blood pressure and protein excretion rate, lowering of blood lipids, tight glucose control for diabetics, and lifestyle changes form part of the future multimodal protocol for management of patients with chronic nephropathies.

Strategies for national health care systems in emerging countries: The case of screening and prevention of renal disease progression in Bolivia. There are close to 1 million people in the world who are alive simply because they have access to one form or another of renal replacement therapy (RRT). Ninety percent live in high-income countries. Little is known of prevalence and incidence of chronic kidney disease and of end-stage renal disease (ESRD) in middle-income and low-income countries, where the use of RRT is scarce or nonexistent. However, no intervention is undertaken, these people will experience progression to ESRD and death from uremia, because RRT is out of reach for them. These are the individuals for whom efforts should be focused to prevent or delay progression toward ESRD. Abstract In 1992, the Mario Negri Institute for Pharmacological Research in Bergamo, Italy, with the cooperation of the young doctors of the Ospedale Giovanni XXIII in La Paz (Bolivia), activated a specific project titled “El Proyecto de Enfermedades Renales en Bolivia” (The Project for Renal Diseases in Bolivia). The project sought to demonstrate that in emerging countries the best strategies against renal disease are prevention and early detection. After proper training of local personnel at the Clinical Research Center “Aldo e Cele Dacco” of the Mario Negri Institute in Bergamo, Italy, an educational campaign titled “First Clinical and Epidemiological Program of Renal Diseases”—under the auspices of the Renal Sister Center Program of the International Society of Nephrology—was conducted in 3 selected areas of Bolivia, including tropical, valley, and plains areas. The goal was to define the frequency of asymptomatic renal disease in these areas by screening a large population of patients at relatively low costs. The screening was formally performed at first-level health centers (Unidad de Salud). Participants were instructed to void a clean urine specimen, and a dipstick test was performed. Patients with positive urinalysis were enrolled in a follow-up program with subsequent laboratory and clinical checks. The study was conducted by 21 clinical centers. Apparently healthy patients (14,082) were enrolled over a period of 7 months. Urinary abnormalities were found on first screening in 4261 patients, but only 1019 patients (23.9%) were available for follow-up. At second urinalysis, 35% of patients had no abnormalities. In the remaining positive group of patients, further investigations disclosed the following abnormalities: urinary tract infection (48.4%), isolated hematuria (43.9%), chronic renal failure (1.6%), renal tuberculosis (1.6%), and other diagnoses 4.3% (kidney stones, 1.3%; diabetic nephropathy, 1%; polycystic kidney diseases, 1.9%). Abstract The experience gained from this initial screening program formed the basis for a second study aimed to prevent renal disease progression in a selected Bolivian population with high altitude polycythemia. Abstract In conclusion, our studies show that mass screening of the population for renal disease is feasible in developing countries and can provide useful information on frequency of renal diseases. Also, in patients with altitude polycythemia, long-term treatment with low doses of enalapril safely prevents increase in arterial blood pressure and progressively reduces hematocrit and proteinuria. Aside from its scientific value, this last study can be taken as an example of how, by rationalizing resources and investing in research programs, renal disease progression and cardiovascular risk may eventually improve, which ultimately should translate into less demand for dialysis, and thus provide alternatives to costly RRT. The transformation of the Bolivian pilot model into a systematic program applicable to most emerging countries may be seen as a task of national nephrology societies, along with methodologic and economic support of international bodies.

Renal replacement therapy by hemodialysis, peri- toneal dialysis, or renal transplantation prolongs survival in patients with end-stage renal disease (ESRD) and, in most cases, provides a good quality of life. In all rich coun- tries, new dialysis patients outnumber those who die, and the group of patients on renal replacement therapy is growing. The provision of adequate treatment to all is ab- sorbing a large proportion of the health care budget and is being looked at with concern by policymakers. Since rationing of dialysis or deciding that some patients can- not be treated is out of the question, clinicians should be looking for ways to prevent the need for dialysis in as many patients as possible. an important correlation between urinary protein ex- cretion and rate of glomerular filtration rate (GFR) de- cline in patients with diabetic (5) and nondiabetic chronic nephropathy (6). The role of proteinuria as a strong, in- dependent predictor of ESRD has been also recently documented in a mass screening setting (7). By screen- ing more than 100,000 healthy individuals in 1983 in Okinawa, Japan, and following them for up to 17 years, a positive relationship was found between baseline pro- teinuria (by dipstick urine test) and the risk of developing ESRD. Even a slight increase in proteinuria was an inde- pendent risk factor for ESRD. Moreover, the predictive value of the protein excretion rate was independent of the baseline GFR levels (abstract; Iseki K et al, JA m Soc Nephrol 14:194A, 2003). Whenever proteinuria is decreased, progression to ESRD is reduced (8, 9-11). Results of the Modification of Diet in Renal Disease (MDRD) study (8) established that a reduction of proteinuria was associated with a decrease in the rate of decline in GFR, and that the protection of renal function achieved by lowering blood pressure was dependent on the extent of initial proteinuria. The role of proteinuria as a promoter of progression, and its impact on renal outcome, was also explored by the Ramipril Efficacy in Nephropathy (REIN) study (11). This study was designed to assess the hypothesis that ACE inhibition could be superior to other antihyperten- sive drugs in reducing proteinuria, limiting the decline in GFR, and preventing ESRD in patients with chronic nephropathies. In this study, patients were randomly as- signed to receive ramipril or conventional antihyperten- sive therapy to maintain diastolic blood pressure at 90 mm Hg or less. A prestratification strategy recognized 2 levels of proteinuria (stratum 1: >1 and

The growing global burden of noncommunicable diseases worldwide has been neglected by policy makers, major aid donors, and academics. In 2003, there were 56 million deaths globally, 60% of which were due to noncommunicable diseases [1]. These chronic diseases are the largest cause of the death in the world, led by cardiovascular disease (17 million deaths in 2002, mainly from ischemic heart disease and stroke), followed by cancer (7 million deaths), chronic lung disease (4 million), and diabetes mellitus (almost 1 million) [2]. These leading diseases share key risk factors: tobacco use, unhealthy diets, lack of physical activity, and alcohol abuse [1]. The current burden of chronic diseases reflects past exposure to these risk factors, and the future burden will be largely determined by current exposures. The global prevalence of these chronic diseases is increasing, with the majority occurring in developing countries and projected to increase substantially over the next two decades [3]. Cardiovascular disease (CVD) is already the leading cause of mortality in developing countries. Between 1990 and 2020, mortality from ischemic heart disease in developing countries is expected to increase by 120% for women and 137% for men [4]. Predictions for the next two decades include a near tripling of ischemic heart disease and stroke mortality in Latin America, the Middle East, and subSaharan Africa. The global number of individuals with diabetes in 2000 was estimated to be 171 million (2.8% of the world’s population), a figure projected to increase in 2030 to 366 million (6.5%), 298 million of whom will live in developing countries. Risks for chronic diseases are also escalating. Smoking prevalence and obesity levels among adolescents in developing countries have risen considerably over the past decade and portend rapid increase in chronic diseases [5, 6]. Numerous developing countries and countries in transition have witnessed a rapid deterioration of their chronic disease risk and mortality profiles [1]. In the world’s most populous country, China, age-specific death rates from circulatory disease increased between 200% and 300% in those aged 35

Chronic kidney diseases are emerging as a global threat to human health. More than 1 million people worldwide are alive on renal dialysis or with a functioning graft ([1][1]). The incidence of renal failure has doubled during the past 15 yr, a trend that is likely to continue in the next decade. It

Idiopathic membranous nephropathy (MN) has a variable rate of progression to end-stage renal failure, with a significant number of patients going into spontaneous remission without therapy. For those who have persistent nephrotic proteinuria or manifest deterioration of renal function, steroids and immunosuppressive drugs are used. However, their long-term efficacy is challenged by a meta-analysis presented here. A different approach to reduction of proteinuria, a recognized progression promoter, is based on the notion that angiotensin II inhibition controls proteinuria and slows progression. Further, a more complex approach is required than simple administration of an angiotensin-converting enzyme (ACE) inhibitor: a multidrug approach to remission of nephrotic syndrome therefore is described here.

A 60-year-old man with recently diagnosed type 2 diabetes mellitus has a serum creatinine level of 1.5 mg per deciliter (133 μmol per liter), and a dipstick test shows proteinuria (++). His blood pressure is 150/90 mm Hg. He smokes half a pack of cigarettes daily. What can be done to reduce the risk of progressive renal disease?

Background. In Italy, the project on the social burden and quality of life (QoL) of patients with haemophilia investigates costs from a society perspective and provides an overview of their quality of life. Moreover, as life expectancy increased in recent years along with new treatment strategies implemented in the last decades, it analyses trends of costs other than drugs simulating impacts during patient whole life. Material and methods. We ran a web-based cross-sectional survey supported by the Italian Federation of Haemophilia Societies in recruiting patients with haemophilia and their caregivers. We developed a questionnaire to collect information on demographic characteristics, healthcare and social services consumption, formal and informal care utilisation, productivity loss and quality of life. In particular, quality of life was assessed through the EuroQoL tool. Last, we applied the illness cost method from a society perspective. Results. On average, quality of life is worse in adult patients compared to child and caregivers: more than 75% of adult patients declare physical problems, 43% of adult patients and 54% of their parents have anxiety problems. Assuming a society perspective, the estimated mean annual total cost per patient in 2012 is 117,732 €. Drugs represent 92% of total costs. Focusing on costs other than drugs, each additional point of EuroQoL tool implies a costs' reduction of 279 €. The impact of age varies across age groups: each added year implies a total decrease of costs up to 46.6 years old. Afterwards, every additional year increases costs. Discussion. Quality of life of patients with haemophilia and their caregivers improved and it influences positively on consumed resources and on their contribution to the social-economic system. Costs other than drugs for patients with haemophilia follow the same trends of general population. © SIMTI Servizi Srl.

Rare diseases aff ect a limited number of individuals (defi ned as no more than one in 2000 individuals in the European Union and no more than about one in 1250 in the USA), but the number of disorders that fi t this defi nition is very large (>5000 according to WHO). Therefore, the number of patients aff ected by a rare disease could be about 30 million in Europe and 25 million in North America. The true burden of rare diseases in Europe and elsewhere is diffi cult to estimate, since epidemiological data for most of these diseases are not available. Rare diseases are an important public-health issue and a challenge for the medical community. They are called health orphans, because rare diseases were neglected for many years. Similarly, before the USA passed the Orphan Drug Act in 1983, the pharmaceutical industry had neglected the development of treatments for rare diseases, hence the name orphan drugs. Public awareness about the diffi culties of patients with rare diseases was fi rst raised by the report of the National Commission on Orphan Disease of the US Government in 1989. The Commission’s hearings with hundreds of stakeholders highlighted issues that aff ected patients’ care, such as little information on rare diseases, diffi culties of fi nancing research, drawbacks of providing adequate health insurance and coverage of medical expenses, and the limited availability of eff ective treatments. The International Classifi cation of Diseases (ICD) that is used in most countries is not convenient for rare diseases. The absence of a universally recognised coding system is an obstacle for reliable registration of patients in national or international databases, preventing assessment of the economic and social eff ects of rare diseases. For some disorders, national or international registries are available, which have been set up and maintained by researchers, patients’ associations, public institutions, or drug companies. The European Rare Disease Task Force of the Health and Consumers Protection Directorate General of the European Commission has set up a working group to collaborate with WHO on ICD-10, and is considering all other existing classifi cations to provide the rare-diseases community with a uniform system. Assessment of the prevalence of rare diseases was attempted by the European Organization for Rare Diseases (Eurordis), and Orphanet, with the support of the European Commission. This study not only provided an estimate of the prevalence of several rare diseases (table), but also showed the absence of reliable data, low consistency between sources of information, and poor methodological quality of epidemiological studies. Additionally, facilities for biochemical or genetic testing are scarce. We use the collective term of rare diseases to include a very heterogeneous group of disorders that can aff ect any system. Most rare diseases are genetic disorders, which are often severely disabling, substantially aff ect life expectancy, and impair physical and mental abilities. These disabilities result in reduced quality of life, and aff ect an individual’s potential for education and earning capabilities. One example is inborn errors of metabolism, most of which are rare (prevalence between 1 in 1400 and 1 in 5000 livebirths). An Italian prospective study (1985–97) on patients aged 0–17 years revealed that, of the 1935 newborn babies with inborn errors of metabolism identifi ed by the study, only 11% reached adulthood. Rare diseases also pose a considerable burden on the aff ected families. This burden was assessed by sending a questionnaire to 2500 patients with chronic diseases (8·2% of which were rare diseases). Patients with rare disorders had the worst exper ience in terms of loss of social and economic oppor tunities, and of medical care. Patients with rare diseases face diagnostic delays. This issue was shown in a survey of eight rare diseases (Crohn’s disease, cystic fi brosis, Duchenne muscular dystrophy, Ehlers-Danlos syndrome, Marfan’s syndrome, Prader-Willi syndrome, tuberous sclerosis, and Lancet 2008; 371: 2039–41

Idiopathic membranous nephropathy is one of the most commonly encountered forms of nephrotic syndrome in adults. The natural history of the disease, observed in a small sample of untreated patients, reveals that a large proportion of patients experience spontaneous remission, whereas approximately one third of them progress towards renal insufficiency, and thus require dialysis. Hence, several attempts to treat this condition have been investigated and several protocols, based on different combinations of corticosteroids and/or immunosuppressive agents, have been proposed. However, none of these protocols has been uniformly adopted by renal physicians, either because of no or limited efficacy of most of them, or due to the potential of short- and long-term untoward effects. In this review, we examine the available data on the natural course of the disease and the possibility of identifying clinical and laboratory characteristics that could help to predict the course of membranous nephropathy. We also summarise the results of the most relevant clinical trials, and offer an updated meta-analysis of treatment studies, including the latest data on cyclosporin.

Although in some parts of the world acute and chronic kidney diseases are preventable or treatable disorders, in many other regions these diseases are left without any care. The nephrology community needs to commit itself to reduction of this divide between high-income and low-income regions. Moreover, new and exciting developments in fields such as pharmacology, genetic, or bioengineering, can give a boost, in the next decade, to a new era of diagnosis and treatment of kidney diseases, which should be made available to more patients.

Objectives The BURQOL-RD project is intended to develop a disease based model capable of quantifying the socio-economic burden and health-related quality of life for patients with rare diseases (RDs) and their caregivers in Europe. We described the methodology used to select a set of 10 RDs to be approached in a pilot study. Methods BURQOL-RD project includes 23 partners from 8 European countries: Spain, UK, France, Germany, Sweden, Italy, Hungary and Bulgaria. A two-round Delphi panels in combination with Carroll diagram was used to generate consensus in the selection of the 10 RDs among the project participants. Results The two Delphi rounds yielded a prioritised list, to which the Carroll diagram was applied, taking into account three determinants: prevalence, availability of effective treatment and need for carer. The final set of RD to be studied was obtained: cystic fibrosis, Prader–Willi syndrome, haemophilia, duchenne muscular dystrophy, epidermolysis bullosa, fragile X syndrome, scleroderma, mucopolysaccharidosis, juvenile idiopathic arthritis and histiocytosis. Conclusions This methodology permitted the generation of an equilibrated set of RDs for the pilot study of BURQOL-RD project. The model will be suitable for application in a wide range of RDs.

The treatment of membranous nephropathy, the most common form of glomerular diseases causing nephrotic syndrome in adults, is still debated. A considerable percentage of patients have a spontaneous remission of the disease and reduction of urinary protein excretion with time. Studies in the past have indicated that prednisone may have beneficial effects, but this has not been confirmed by more recent investigation. Others have studied the association of methylprednisolone with cyclophosphamide or chlorambucil, but results are conflicting. The main reasons for the conflicting data are the variety of clinical presentations of the disease and the different study populations. Most trials performed so far have not included enough patients in each category to adequately detect differences between treatment groups and placebo groups. Several studies with few numbers of patients reported that cyclosporine effectively reduced proteinuria and may have less long-term toxicity than more conventional immunosuppressants. This finding, however, must be verified by appropriate clinical trials.

Under the term "autoimmune diseases" are comprised a large number of disorders with variable clinical expression which have in common an autoimmune pathogenesis as defined by direct, indirect or circumstantial evidence. Autoimmune diseases may affect a single organ or may determine a multisystem involvement, and most of them cause significant and chronic morbidity and disability. Another important feature of autoimmune diseases is their propensity to affect more often females than males. Although few of them are quite common and well studied, the majority of autoimmune diseases are rare, and share with rare diseases lack of epidemiology data. The implementation of specific disease registries can help improve the knowledge on epidemiology of these conditions, a crucial step for evaluating health care interventions.

Background 'Compassionate use' programmes allow medicinal products that are not authorised, but are in the development process, to be made available to patients with a severe disease who have no other satisfactory treatment available to them. We sought to understand how such programmes are regulated in ten European Union countries. Methods The European Clinical Research Infrastructures Network (ECRIN) conducted a comprehensive survey on clinical research regulatory requirements, including questions on regulations of 'compassionate use' programmes. Ten European countries, covering approximately 70% of the EU population, were included in the survey (Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and the UK). Results European Regulation 726/2004/EC is clear on the intentions of 'compassionate use' programmes and aimed to harmonise them in the European Union. The survey reveals that different countries have adopted different requirements and that 'compassionate use' is not interpreted in the same way across Europe. Four of the ten countries surveyed have no formal regulatory system for the programmes. We discuss the need for 'compassionate use' programmes and their regulation where protection of patients is paramount. Conclusions 'Compassionate use' is a misleading term and should be replaced with 'expanded access'. There is a need for expanded access programmes in order to serve the interests of seriously ill patients who have no other treatment options. To protect these patients, European legislation needs to be more explicit and informative with regard to the regulatory requirements, restrictions, and responsibilities in expanded access programmes.

Under the term “autoimmune diseases” are comprised a large number of disorders with variable clinical expression which have in common an autoimmune pathogenesis as defined by direct, indirect or circumstantial evidence. Autoimmune diseases may affect a single organ or may determine a multisystem involvement, and most of them cause significant and chronic morbidity and disability. Another important feature of autoimmune diseases is their propensity to affect more often females than males. Although few of them are quite common and well studied, the majority of autoimmune diseases are rare, and share with rare diseases lack of epidemiology data. The implementation of specific disease registries can help improve the knowledge on epidemiology of these conditions, a crucial step for evaluating health care interventions.

Fast atom bombardment mass spectrometry was used to characterize phospholipids from tubuli and glomeruli of normal rats and rats with acute renal failure. It was possible to assess the molecular species of the principal phospholipidic classes. In all of them, the most abundant species contained a residue of arachidonic acid. The phospholipids of urine were also analyzed, showing the presence of the major molecular species of several phospholipid classes. Excretion of phospholipids was greater in urine from rats with acute renal failure.

End-stage renal disease (ESRD) is a global health problem. There are differences in mortality among patients with ESRD amid industrialized countries that may be related to their respective systems of delivery of care. A nationwide survey was completed in Italy, a country with low mortality rate for ESRD patients, in order to help understand key aspects of ESRD delivery of care that contribute to mortality. Survey responses were obtained and analyzed from 131 of 575 dialysis centers (23%), covering data from 13,170 dialysis patients in 2006. The mortality rate was 11.2% and the prevalence of diabetes-associated kidney disease was 21%. Of the patients, 88% were on hemodialysis and 12% were on peritoneal dialysis. Most patients were in the age range of 65–75 years (66.7%), were seen by a nephrologist at CKD stage 3, and began dialysis at mean estimated GFR of 9.6 ml/min/1.73 m2. AV fistulae were the prevailing form of vascular access (83%) and were most frequently placed by a nephrologist (61.2%). In 98% of the dialysis centers, a nephrologist was present during dialysis sessions. The following may explain the low mortality for ESRD patients in Italy: low prevalence of diabetes, high use of AV fistulae, delivery of care by nephrologists beginning in pre-ESRD stages, their involvement in placement of dialysis vascular access, and their physical presence requirement during dialysis sessions. These findings portray key aspects of the contemporary delivery of care for Italian dialysis patients and provide a platform for international comparison of healthcare systems for ESRD.

Background Thorough knowledge of the regulatory requirements is a challenging prerequisite for conducting multinational clinical studies in Europe given their complexity and heterogeneity in regulation and perception across the EU member states. Methods In order to summarise the current situation in relation to the wide spectrum of clinical research, the European Clinical Research Infrastructures Network (ECRIN) developed a multinational survey in ten European countries. However a lack of common classification framework for major categories of clinical research was identified, and therefore reaching an agreement on a common classification was the initial step in the development of the survey. Results The ECRIN transnational working group on regulation, composed of experts in the field of clinical research from ten European countries, defined seven major categories of clinical research that seem relevant from both the regulatory and the scientific points of view, and correspond to congruent definitions in all countries: clinical trials on medicinal products; clinical trials on medical devices; other therapeutic trials (including surgery trials, transplantation trials, transfusion trials, trials with cell therapy, etc.); diagnostic studies; clinical research on nutrition; other interventional clinical research (including trials in complementary and alternative medicine, trials with collection of blood or tissue samples, physiology studies, etc.); and epidemiology studies. Our classification was essential to develop a survey focused on protocol submission to ethics committees and competent authorities, procedures for amendments, requirements for sponsor and insurance, and adverse event reporting following five main phases: drafting, consensus, data collection, validation, and finalising. Conclusion The list of clinical research categories as used for the survey could serve as a contribution to the, much needed, task of harmonisation and simplification of the regulatory requirements for clinical research in Europe.

A tendency toward thrombosis (particularly of the arterovenous shunt) is a frequent complication of uremic patients on hemodialysis. It is well known that uremia is associated with complex coagulation abnormalities (1, 2, 3, 4) which include both bleeding diathesis (for a review see chapter by Winchester JF) and hypercoagulability. Table 1 shows the factors involved in the latter disturbance. The results of the global coagulation screening tests in uremic patients are generally normal. Most consistent findings are an increased level of fibrinogen (5) and decreased protein C anticoagulant activity with normal amidolytic activity and antigen (6, 7). Recently, it has been documented that the reduced protein C anticoagulant activity is due to the presence of a soluble plasma inhibitor that interferes specifically with the anticoagulant activity of activated protein C (8). Given the role of fibrinogen and protein C in coagulation homeostasis, it is not surprising that these abnormalities contribute to the increased risk of thrombosis episodes in these patients. In vivo studies have also demonstrated enhanced platelet activity in this population (9, 10, 11).