Current status of transplantation and organ donation in the Balkans--could it be improved through the South-eastern Europe Health Network (SEEHN) initiative?

Organ donation and transplantation activity in the majority of Balkan countries (Albania, Bosnia and Herzegovina, Croatia, Macedonia, Moldova, Montenegro, Serbia, Romania and Bulgaria) are lagging far behind international averages. Inadequate financial resources, unclear regional data and lack of government infrastructure are some of the issues which should be recognized to draw attention and lead to problem-solving decisions. The Regional Health Development Centre (RHDC) Croatia, a technical body of the South-eastern Europe Health Network (SEEHN), was created in 2011 after Croatia's great success in the field over the last 10 years. The aim of the RHDC is to network the region and provide individualized country support to increase donation and transplantation activity in collaboration with professional societies (European Society of Organ Transplantation, European Transplant Coordinators Organization, The Transplantation Society and International Society of Organ Donation and Procurement). Such an improvement would in turn likely prevent transplant tourism. The regional data from 2010 show large discrepancies in donation and transplantation activities within geographically neighbouring countries. Thus, proposed actions to improve regional donation and transplantation rates include advancing living and deceased donation through regular public education, creating current and accurate waiting lists and increasing the number of educated transplant nephrologists and hospital coordinators. In addition to the effort from the professionals, government support with allocated funds per deceased donation, updated legislation and an established national coordinating body is ultimately recognized as essential for the successful donation and transplantation programmes. By continuous RHDC communication and support asked from the health authorities and motivated professionals from the SEEHN initiative, an increased number of deceased as well as living donor kidney transplantations in the future should be more realistic.

Trafficking in Human Beings for the Purpose of Organ Removal and the Ethical and Legal Obligations of Healthcare Providers.

Physicians and other health care professionals seem well placed to play a role in the monitoring and, perhaps, in the curtailment of the trafficking in human beings for the purpose of organ removal. They serve as important sources of information for patients and may have access to information that can be used to gain a greater understanding of organ trafficking networks. However, well-established legal and ethical obligations owed to their patients can create challenging policy tensions that can make it difficult to implement policy action at the level of the physician/patient. In this article, we explore the role-and legal and ethical obligations-of physicians at 3 key stages of patient interaction: the information phase, the pretransplant phase, and the posttransplant phase. Although policy challenges remain, physicians can still play a vital role by, for example, providing patients with a frank disclosure of the relevant risks and harms associated with the illegal organ trade and an honest account of the physician's own moral objections. They can also report colleagues involved in the illegal trade to an appropriate regulatory authority. Existing legal and ethical obligations likely prohibit physicians from reporting patients who have received an illegal organ. However, given the potential benefits that may accrue from the collection of more information about the illegal transactions, this is an area where legal reform should be considered.

Prevention of Transnational Transplant-Related Crimes-What More Can be Done?

BACKGROUND: Many nations are able to prosecute transplant-related crimes committed in their territory, but transplant recipients, organ sellers and brokers, and transplant professionals may escape prosecution by engaging in these practices in foreign locations where they judge the risk of criminal investigation and prosecution to be remote. METHODS: The Declaration of Istanbul Custodian Group convened an international working group to evaluate the possible role of extraterritorial jurisdiction in strengthening the enforcement of existing laws governing transplant-related crimes across national boundaries. Potential practical and ethical concerns about the use of extraterritorial jurisdiction were examined, and possible responses were explored. RESULTS: Extraterritorial jurisdiction is a legitimate tool to combat transplant-related crimes. Further, development of a global registry of transnational transplant activities in conjunction with a standardized international referral system for legitimate travel for transplantation is proposed as a mechanism to support enforcement of national and international legal tools. CONCLUSIONS: States are encouraged to include provisions on extraterritorial jurisdiction in their laws on transplant-related crimes and to collaborate with professionals and international authorities in the development of a global registry of transnational transplant activities. These actions would assist in the identification and evaluation of illicit activities and provide information that would help in developing strategies to deter and prevent them.

Chronic kidney disease and cardiovascular risk in six regions of the world (ISN-KDDC): a cross-sectional study.

BACKGROUND: Chronic kidney disease is an important cause of global mortality and morbidity. Data for epidemiological features of chronic kidney disease and its risk factors are limited for low-income and middle-income countries. The International Society of Nephrology's Kidney Disease Data Center (ISN-KDDC) aimed to assess the prevalence and awareness of chronic kidney disease and its risk factors, and to investigate the risk of cardiovascular disease, in countries of low and middle income. METHODS: We did a cross-sectional study in 12 countries from six world regions: Bangladesh, Bolivia, Bosnia and Herzegovina, China, Egypt, Georgia, India, Iran, Moldova, Mongolia, Nepal, and Nigeria. We analysed data from screening programmes in these countries, matching eight general and four high-risk population cohorts collected in the ISN-KDDC database. High-risk cohorts were individuals at risk of or with a diagnosis of either chronic kidney disease, hypertension, diabetes, or cardiovascular disease. Participants completed a self-report questionnaire, had their blood pressure measured, and blood and urine samples taken. We defined chronic kidney disease according to modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria; risk of cardiovascular disease development was estimated with the Framingham risk score. FINDINGS: 75,058 individuals were included in the study. The prevalence of chronic kidney disease was 14·3% (95% CI 14·0-14·5) in general populations and 36·1% (34·7-37·6) in high-risk populations. Overall awareness of chronic kidney disease was low, with 409 (6%) of 6631 individuals in general populations and 150 (10%) of 1524 participants from high-risk populations aware they had chronic kidney disease. Moreover, in the general population, 5600 (44%) of 12,751 individuals with hypertension did not know they had the disorder, and 973 (31%) of 3130 people with diabetes were unaware they had that disease. The number of participants at high risk of cardiovascular disease, according to the Framingham risk score, was underestimated compared with KDIGO guidelines. For example, all individuals with chronic kidney disease should be considered at high risk of cardiovascular disease, but the Framingham risk score detects only 23% in the general population, and only 38% in high-risk cohorts. INTERPRETATION: Prevalence of chronic kidney disease was high in general and high-risk populations from countries of low and middle income. Moreover, awareness of chronic kidney disease and other non-communicable diseases was low, and a substantial number of individuals who knew they were ill did not receive treatment. Prospective programmes with repeat testing are needed to confirm the diagnosis of chronic kidney disease and its risk factors. Furthermore, in general, health-care workforces in countries of low and middle income need strengthening. FUNDING: International Society of Nephrology.

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.

The future of renoprotection.

Chronic kidney diseases are emerging as a global threat to human health. Renal replacement therapy by 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 wealthy countries, new patients on dialysis outnumber those who die, and the group of patients on renal replacement therapy is growing. The provision of adequate treatment to all is absorbing a large proportion of the health care budget and is being looked at with concern by policymakers. Because rationing of dialysis or deciding that some patients cannot 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. Simple and inexpensive treatments are plausible and possibly effective. There is robust experimental evidence that proteinuria is responsible for interstitial inflammation and subsequent fibrosis, which thereby contributes to progressive renal function loss. Clinical studies and clinicopathologic correlations in patients with progressive nephropathies indicate that observations in experimental models are relevant to understanding human disease. Researchers have identified an important correlation between urinary protein excretion and rate of glomerular filtration rate decline in patients with diabetic and nondiabetic chronic nephropathy. Renoprotection is a strategy that aims to interrupt or reverse this process. The current therapeutic approach for proteinuric chronic nephropathies is based on blockade of the renin-angiotensin system with angiotensin converting-enzyme inhibitors and/or angiotensin-receptor blockers that limit proteinuria, and reduce glomerular filtration rate decline and risk of ESRD more effectively than other antihypertensive treatments. Full remission of the disease, however, is seldom obtained, particularly when pharmacologic intervention is started late. For those who do not respond, treatment procedures to achieve remission and/or regression must include a multimodel strategy to implement renoprotection. The role of lifestyle changes, including smoking cessation, should not be overlooked. A more concerted, strategic, and multisectorial approach, underpinned by solid research evidence, is essential to help reverse the increasing incidence of these chronic diseases, not just for a few beneficiaries, but equitably and on a global scale.

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. 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%). 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. 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.

Cyclosporine prolongs delayed graft function in kidney transplantation: are rabbit anti-human thymocyte globulins the answer?

BACKGROUND: Cyclosporine (CsA) nephrotoxicity may prolong duration of anuria in renal transplant patients with delayed graft function (DGF). Thus, many Transplant Centers tend to delay CsA treatment in order to accelerate renal function recovery. METHODS: In this single-center, retrospective analysis we compared the outcomes of 40 renal transplant patients with DGF given a CsA-based (n = 17) regimen since the day of transplant or a CsA-sparing regimen (n = 23) based on early treatment with rabbit anti-human thymocyte globulin (RATG) and delayed CsA administration. We studied all patients with DGF who received a first or second graft at the Bergamo Transplant Center from January 1992 to March 2000. RESULTS: Patients given RATG as compared to those on CsA had significantly shorter duration of anuria (11.0 +/- 5.6 vs. 19.6 +/- 8.9 days; p < 0.005) and of initial hospitalization (17.4 +/- 4.3 vs. 27.4 +/- 10.4 days; p < 0.001). Throughout the whole study period, 4 patients on RATG as compared to 6 on CsA had an acute rejection episode (p > 0.05). However, no patient on RATG as compared to 4 on CsA had an acute rejection during the anuria period (p < 0.05). Costs including hospitalization, dialysis treatment and study drugs were significantly lower in RATG than in CsA patients (EUR 29,944 +/- 7,281 vs. 36,795 +/- 13,656; p < 0.05). CONCLUSIONS: In renal transplant patients with DGF, early RATG treatment with delayed CsA administration accelerated renal function recovery and patient discharge, prevented occult rejections throughout the anuria period and significantly decreased the treatment costs.

Prevalence of hypertension and diabetes and coexistence of chronic kidney disease and cardiovascular risk in the population of the republic of moldova.

In 2005, the International Society of Nephrology (ISN) established the Global Outreach Program (GO) aimed at building a capacity for detecting and managing chronic kidney disease and its complications in low- and middle-income countries. Here we report data from the 2006-2007 screening program (1025 subjects from the general population) in the Republic of Moldova aimed to determine the prevalence of hypertension, diabetes, and their coexistence with microalbuminuria. The likelihood of a serious cardiovascular (CV) event was also estimated. Hypertension and diabetes were very common among screened subjects. The prevalence of microalbuminuria was 16.9% and that of estimated GFR <60 ml/min/1.73 m(2) (decreased renal function) was 9.4%. Male gender was associated with an increased prevalence of hypertension and microalbuminuria. Hypertension and diabetes clustered in subjects with microalbuminuria and renal dysfunction. Risk factors such as preobesity/obesity, physical inactivity and smoking were relatively common, even in younger participants. The prevalence of subjects with predicted 10-year CV risk ≥10% was 10.0%. In conclusion, in the Republic of Moldova patients with hypertension and diabetes should be screened for the coexistence of renal abnormalities, with the intention of developing disease-specific health-care interventions with the primary goal to reduce CV morbidity and mortality and prevent renal disease progression to end stage renal disease.

Basiliximab combined with low-dose rabbit anti-human thymocyte globulin: a possible further step toward effective and minimally toxic T cell-targeted therapy in kidney transplantation.

In high-risk kidney transplant recipients, induction therapy with rabbit anti-human thymocyte globulin (RATG) reduces the risk for acute rejection but is associated with significant toxicity, opportunistic infections, and cancer. Using reduced doses of RATG combined with anti-IL-2 antibodies may achieve the same antirejection activity of standard-dose RATG but with a better safety profile. This randomized, open-label study compared the efficacy, tolerability, and costs of low-dose RATG (0.5 mg/kg per d) plus basiliximab (20 mg 4 d apart) versus standard-dose RATG (2 mg/kg per d) in 33 consecutive high-risk renal transplant recipients (living-related transplant recipients, sensitized patients or patients who received another transplant, and patients with delayed graft function) over 6 mo of follow-up. All patients received concomitant therapy with steroids, cyclosporin A, and azathioprine or mycophenolate mofetil. Seventeen patients received low-dose RATG plus basiliximab, and 16 received standard-dose RATG. Patient (100 versus 100%) and graft (94 versus 100%) survival were comparable in the two groups, but the incidence of fever (17.6 versus 56.5%; P = 0.01), leukopenia (23.5 versus 56.3%; P < 0.05), anemia (29.4 versus 62.5%; P < 0.05), cytomegalovirus reactivations (17.6 versus 56.5%; P = 0.01), the number of transfused units (0.5 +/- 0.9 versus 2.0 +/- 2.4; P < 0.001), and treatment costs (3652 +/- 704 versus 5400 +/- 1960 euro; P = 0.001) were lower with low-dose RATG plus basiliximab than with standard-dose RATG. There was one episode of biopsy-proven acute rejection on low-dose RATG plus basiliximab, and there were two on standard-dose RATG. In renal transplantation, induction therapy with basiliximab plus low-dose RATG effectively prevents acute rejection and is safer and more cost-effective than induction with standard-dose RATG.

Prevention programmes of progressive renal disease in developing nations.

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.

Dual blockade of the renin-angiotensin system: the ultimate treatment for renal protection?

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 the renin-angiotensin system both by angiotensin-converting enzyme 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 for doubling baseline serum creatinine or progression toward end-stage renal failure in patients who do and do not have diabetes and have chronic nephropathies that are treated with angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists. However, the number of patients who reach end-stage renal failure is still considerably high. Significant reduction of the incidence of ESRD is likely to be achieved in the near future for chronic nephropathies, provided that the degree of renoprotection can be improved. 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 BP and protein excretion rate, lowering of blood lipids, tight glucose control for individuals with diabetes, and lifestyle changes form part of the future multimodal protocol for treatment of patients with chronic nephropathies.

Hyperuricemia in kidney transplantation.

Hyperuricemia is a common problem among renal transplant recipients. Its prevalence is clearly attributable to cyclosporine (CsA) use, although individual patients may have other risk factors as well. CsA lowers the urinary clearance of uric acid. The specific mechanism for this is unknown, but may involve alteration in tubular transport. Hyperuricemia may add on to several other factors in contributing to progressive deterioration of graft function and ultimately graft loss. The therapy of hyperuricemia may be particularly challenging in transplant patients.