- Email: [email protected]
The future of renoprotection
Kidney International, Vol. 68, Supplement 97 (2005), pp. S95–S101
The future of renoprotection NORBERTO PERICO, IGOR CODREANU, ARRIGO SCHIEPPATI, and GIUSEPPE REMUZZI Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo-Mario Negri Institute for Pharmacological Research, Bergamo, Italy; and Department of Hemodialysis and Kidney Transplantation, Republican Clinical Hospital, Chisinau, Moldova
cronica ´ (IRC) y en su mayor parte, proveen de una buena calidad de vida. En los pa´ıses desarrollados el numero ´ de pacientes nuevos en dialisis ´ sobrepasa al de los que fallecen, por lo que el numero ´ de pacientes en dialisis ´ va en aumento. Es motivo de preocupacion ´ el que la provision ´ de un tratamiento adecuado a todo aquel que lo necesita, este consumiendo un elevado porcentaje de los presupuestos destinados a la atencion ´ de la salud. Dado de que esta´ fuera de consideracion ´ el racionar o el decidir que pacientes no reciban tratamiento dial´ıtico, debemos de buscar las medidas necesarias que prevengan el uso de dialisis ´ en tantos pacientes como sea posible. Es factible y posible el utilizar tratamientos sencillos y de bajo costo. Existe una solida ´ evidencia experimental de que la proteinuria es responsable de la inflamacion ´ y subsiguiente fibrosis del intersticio renal, contribuyendo de esta forma al deterioro de la funcion ´ renal. Estudios cl´ınicos realizados en pacientes con nefropat´ıas progresivas, indican que las observaciones hechas en animales de experimentacion ´ son relevantes al estudio de la enfermedad en humanos. Se ha encontrado una importante correlacion ´ entre la proteinuria y la disminucion ´ en la velocidad de filtracion ´ glomerular, tanto en pacientes con nefropat´ıa diabetica ´ como no diabetica. ´ La renoproteccion ´ es una estrategia dirigida a interrumpir o revertir este proceso. El tratamiento actual de las nefropat´ıas cronicas ´ se basa en el concepto de que la utilizacion ´ del bloqueo del sistema renina angiotensina con inhibidores de la ECA y/o bloqueadores del receptor de la angiotensina, disminuye la proteinuria, la perdida de la filtracion ´ glomerular y el riesgo de IRC, en forma mas ´ efectiva que otros farmacos ´ antihipertensivos. Sin embargo, rara vez se obtiene una remision ´ total, especialmente si el tratamiento se inicia en forma tard´ıa. En individuos que no respondan a dicha terapia, se debe de utilizar una estrategia de proteccion ´ renal multiple. ´ Cambios en los habitos ´ de vida del individuo, incluyendo el abandono del tabaco, no deben de ser pasados por alto. Un abordaje concertado, multifactorial y estrategico, ´ sustentado por una solida ´ evidencia cient´ıfica, es indispensable para revertir el incremento en la incidencia de estas enfermedades cronicas, ´ no solo para el beneficio de unos cuantos, sino en una forma globaly equitativa.
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. Resumen Las enfermedades renales cronicas ´ se han constituido en una seria amenaza global a la salud. La dialisis ´ y el trasplante renal prolongan la vida de los pacientes con insuficiencia renal
THE BURDEN OF CHRONIC RENAL DISEASES Chronic kidney diseases are emerging as a global threat to human health [1]. During the last decade, the dialysis population has been growing at an average of 7% per year. There are now approximately 1.1 million people worldwide on renal replacement therapy (RRT) and, according to reliable estimates, the number of patients on maintenance dialysis will double in 10 years (Fig. 1). The
Key words: renoprotection, proteinuria, renin-angiotensin system blockade, chronic kidney disease. C
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2,095,000
1,065,000
426,000
1990
2000
2010
Fig. 1. Global maintenance dialysis population from 1990 to 2010 (modified from [2]).
total cumulative cost for RRT in the next decade will exceed US $1 trillion [2], a surprising figure from any point of view. In the United States, the total Medicare cost for dialysis and transplantation was US $12.7 billion in 1999 and is expected to exceed US $28.3 billion in 2010. Although this sum is 6% of the total Medicare budget, it serves only 0.7% of the Medicare population. In the European Union, the percentage of the health care expenditure absorbed by RRT programs ranges from 0.7% to 1.8%, whereas patients with end-stage renal disease (ESRD) are 0.025% to 0.06% of the total population. Continuing provision of adequate facilities, equipment, and manpower to assist the growing number of patients with ESRD will pose a substantial burden on health care resources in all developed countries in the near future. Thus, the cost and complexity of RRT put it out of reach for low-income countries, which are struggling to provide preventive and therapeutic measures for communicable diseases such as malaria, tuberculosis, acquired immune deficiency syndrome, and tropical disease infections, and have to assign their meager budget to sanitation, vaccine, nutrition, and other basic needs. Contemporary treatment for ESRD is so costly that there is little chance that the vast majority of the world’s population will have access to it. Less-privileged countries simply cannot establish programs for regular RRT for all patients with chronic kidney disease because of its prohibitive cost [3]. How might the global burden of chronic kidney disease be diminished in the future? At the present, there are no definitive cures for most acquired kidney diseases, and there is no reasonable expectation that gene therapy will be available soon enough to treat genetic forms of kidney diseases, such as polycystic kidney disease. Renal transplantation is limited by organ shortage [4], a worldwide problem that is not likely to be resolved by xenotransplantation in the near or immediate future. The best we can do at the present time is to concentrate our efforts on the prevention of progression of renal diseases.
MECHANISMS OF RENAL DISEASE PROGRESSION During the last 20 years, research in animals and people has helped our understanding of the mechanisms by which chronic kidney diseases progresses and has indicated possible preventive methods. A large number of studies established that progressive deterioration of renal function is the result of compensatory glomerular hemodynamic changes in response to nephron loss. In a widely used experimental model of renal mass reduction, the remaining nephrons undergo hypertrophy, reduced arteriolar resistance, and increased glomerular blood flow [5]. There is a lot of experimental and clinical evidence that pharmacologic inhibition of reninangiotensin system with angiotensin-converting enzyme (ACE) inhibitors or with angiotensin II subtype 1 receptor antagonists (ARB) slow the progression of renal failure. In vivo, angiotensin II enhances the vascular tone of both afferent and efferent glomerular arterioles and modulates intraglomerular capillary pressure and glomerular filtration rate (GFR) [6]. Aside from these glomerular hemodynamic effects of angiotensin II, other studies have revealed several nonhemodynamic effects of angiotensin II that may also be important. These findings have suggested that angiotensin II may alter permselective properties of the glomerular capillary barrier by mediating contraction of the foot processes, ultimately changing slit-diaphragm architecture and allowing proteins to escape more easily into the urinary space [7]. Abnormal protein trafficking through the glomerular capillary wall might contribute to progression of renal disease. Indeed, recent data are in support of the possibility that the excessive protein load of podocytes can be a factor underlying progressive injury of these glomerular cells and through their release of transforming growth factor b1, ultimately allowing myofibroblast differentiation of mesangial cells [8]. Moreover, excessive protein reabsorption by proximal tubuli provides further intrinsic toxicity to this nephron segment. Thus, both in vitro and in vivo, protein overload causes increased production of vasoactive and inflammatory mediators such as endothelin-1, monocyte chemoattractant protein-1, normal T cell expressed and secreted, a chemotactic cytokine for monocytes and memory T cells, and osteopontin [9]. The activation of a variety of molecules, such as cytokines, growth factors, and vasoactive substances, may result in abnormal accumulation of extracellular matrix collagen, fibronectin, and other components that are responsible for interstitial fibrosis. Proinflammatory mediators promote local recruitment of macrophages and lymphocytes [10], which, in turn, can stimulate the transformation of interstitial cells into myofibroblasts. Proximal tubular epithelial cells can interact with interstitial fibroblast to promote fibrogenesis via release of profibrogenic molecules [11].
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Glomerular -capillary hypertension
Increased glomerular permeability to macromolecules Increased filtration of plasma proteins
Proteinuria
Excessive tubular reabsorption Nuclear signals for NF-κB-dependent and independent vasoactive and inflammatory genes. Corresponding protein products then released into interstitium Tubular cell transdifferentiation
Fibroblast proliferation
Fibrogenesis Renal scarring
In summary, there is robust experimental evidence that proteinuria is responsible for interstitial inflammation and subsequent fibrosis, thereby contributing to progressive renal function loss (Fig. 2). THE CONCEPT OF RENOPROTECTION In chronic proteinuric nephropathies, if the interstitial inflammatory reaction and subsequent fibrosis were indeed a feature of protein overloading, limiting protein traffic or the biologic effect of excessive tubular protein reabsorption should prevent or slow progression of renal disease. This is precisely what happens in animals treated with ACE inhibitors. The experimental demonstration that the blockade of angiotensin II with ACE inhibitors slowed the progressive loss of renal function in a number of animal models of renal diseases, including diabetic nephropathy [12, 13], offered the opportunity, for the first time, to devise a treatment strategy that was not limited to passively accompanying patients to their destiny of dialysis; instead, it was aimed at preserving renal function as long as possible. The concept of renoprotection has thus emerged. The recent development of a new class of drugs, the angiotensin-receptor blockers (ARBs) has offered a further opportunity to improve renoprotection. The combination of 2 drugs, an ACE inhibitor and an ARB, in an experimental model of chronic nephropathy, was associated with a significant reduction of proteinuria and a trend toward less renal injury than with each drug alone [14]. The near-complete abolition of angiotensin II activity is instrumental to achieve full renal protection. Clinical studies and clinicopathologic correlations in patients with progressive nephropathies indicate that observations in
Fig. 2. Pathophysiology nephropathies.
of
progressive
experimental models are relevant to understanding human disease [15]. Researchers identified an important correlation between urinary protein excretion and rate of GFR decline in patients with diabetic [16] and nondiabetic chronic nephropathy [17]. The role of proteinuria as a strong, independent predictor of ESRD has been recently documented in a mass-screening setting [18]. By screening more than 100,000 healthy patients in 1983 in Okinawa, Japan, and following up with them for up to 17 years, a positive relationship was found between baseline proteinuria (by dipstick urine test) and the risk for developing ESRD. Even a slight increase in proteinuria was an independent risk factor for ESRD. Moreover, the predictive value of the protein excretion rate was independent of baseline GFR levels [19]. Whenever proteinuria is decreased, progression to ESRD is reduced [20–23]. Results of the Modification of Diet in Renal Disease study [20] established that a reduction of proteinuria was associated with a decrease in the rate of decline in GFR, and that 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 [23]. This study was designed to assess the hypothesis that ACE inhibition might be superior to other antihypertensive drugs in reducing proteinuria, limiting the decline in GFR, and preventing ESRD in patients with chronic nephropathies. In this study, patients were randomly assigned to receive ramipril or conventional antihypertensive therapy to maintain diastolic blood pressure at 90 mm Hg or less. A prestratification strategy recognized 2 levels of proteinuria (stratum 1: >1 and <3 g/24 h; stratum 2: =3 g/24
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Remission clinic Targets of the multidrug approach: Blood pressure
<120/80 mm Hg
Proteinuria
<0.3 g/24 h
LDL
<100 mg/dL
LDL + VLDL
<130 mg/dL
HbA1c
<75% (diabetics)
Lifestyle changes Stop smoking, exercise, lower salt, protein, and calories in diet, lose weight Fig. 3. Targets for the remission clinic for chronic nephropathies that can be achieved by multidrug approach and lifestyle changes.
h). The study showed that although blood pressure control was similar in the 2 treatment groups, ACE inhibitor therapy decreased the progression to ESRD by 50% [23, 24]. Patients who had more proteinuria to start with benefited more from blood-pressure–lowering treatment than those who had less proteinuria. A meta-analysis [25] in 1860 patients with chronic nephropathies also recorded that the benefit of ACE inhibition was greatest in patients with high urine protein excretion at baseline. This drug class seems to have a greater antiproteinuric effect than other antihypertensive drugs, despite equal effects on blood pressure; the investigators concluded that proteinuria is the most important modifiable risk factor to slow progression and that reduction of urine protein excretion is the main goal for treatment. The REIN study was continued for 2 years (the REIN follow-up study), during which all patients previously on placebo were switched to ACE inhibitor [24]. In patients who continued to receive ramipril, GFR further decreased to approximately 0.1 mL/min/month during follow-up, a figure similar to that associated with normal aging. Patients who switched from conventional therapy to ramipril also benefited from treatment. One of the most impressive findings of this prolonged follow-up was that after about 36 months of treatment with ramipril, no additional patients progressed to the point of requiring dialysis, whereas patients switched from conventional therapy to ramipril continued to develop ESRD. A breakpoint was sought in the individual GFR slopes of patients receiving continued ramipril therapy to further investigate the nature of time-dependent improvement in GFR change. It could be predicted that after the breakpoint, 10 patients receiving continued ramipril therapy would never progress to ESRD and that those 10 patients had such improved GFR slopes that progression to ESRD would be delayed by about 5 years. The analysis provides evidence that the
tendency of GFR to decline with time can be halted, and remission is achievable in some patients with chronic renal disease. The decade of large clinical trials in nephropathy was closed when the results of 3 important studies were published in the New England Journal of Medicine [26–28]. All 3 studies examined the role of ARBs in type 2 diabetic nephropathy. One study evaluated the renoprotective effect of the ARB irbesartan in patients with hypertension with incipient nephropathy [28]. The goal of the study was the time of onset of overt albuminuria. In 2 years’ followup, only 5.2% of patients receiving 300 mg of irbesartan reached that goal, as compared with 14.9% of patients on placebo. The groups had similar blood pressure control, a finding that suggests that ARBs are renoprotective independently of their antihypertensive effect. The role of ARB in overt diabetic nephropathy was explored in 2 other trials published in 2001 [26, 28]. In both studies, treatment with ARB resulted in a significant reduction of proteinuria, incidence of serum creatinine doubling, and risk of ESRD. Although we have limited our review to only a few clinical studies, several other trials have been published, some of them small, and with little statistical power and short follow-up. However, they all point in one direction: blockade of renin-angiotensin system is beneficial in most chronic nephropathies. This may not be true in overt nephropathy of type 2 diabetes. The results of several clinical trials have shown, with one exception, that no significant difference was found in terms of renoprotection, as measured as prevention of GFR decline over time, between ACE inhibitors and other antihypertensive agents [29]. Indeed, in patients with type 2 diabetic nephropathy, overt proteinuria, and renal insufficiency, an ACE inhibitor was not able to modify renal hemodynamics and glomerular-sieving properties, despite effective blood pressure control [30]. In summary, currently available treatments have uniformly shown that reduction of blood pressure per se is beneficial in patients with type 2 diabetic nephropathy, whereas the effect of renin-angiotensin system blockade is probably less relevant than in type 1 diabetic nephropathy or nondiabetic nephropathies. Nevertheless, the results of the last decade of experiments and trials provide an important platform of knowledge to devise the best strategy in preventing diabetic nephropathy in the next 10 years. WHAT DOES THE FUTURE HOLD FOR RENOPROTECTION? Evidence from clinical trials suggests that the current practice can, at best, postpone ESRD for a few years but will not allow patients to avoid dialysis during their lifetime. Nevertheless, significant reduction of the incidence of ESRD is likely to be achieved in the near future for
Perico et al: The future of renoprotection
nondiabetic 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 pharmacologic intervention. By analogy with other major medical diseases (e.g., cancer, human immunodeficiency virus, and organ transplantation), a multidrug intervention may be the strategy needed to significantly retard dialysis [31]. Experimental data in rat models support this notion [14]. On clinical grounds, there are a few trials that show that the combination of an ACE inhibitor with an ARB affords greater renoprotection than each drug used alone. Preliminary studies in sodium-depleted healthy volunteers and in patients with diabetes with normal renal function recorded greater reduction in blood pressure and greater increases in plasma renin activity after the addition of losartan to enalapril treatment than after doubling the dose of enalapril [32]. An additive antiproteinuric effect of ACE inhibition and angiotensin II receptor antagonism has been reported in normotensive patients with immunoglobulin A nephropathy; systemic blood pressure was not affected [33]. The COOPERATE study [34] compared a combined treatment of ACE inhibitor and angiotensin II receptor blocker, with monotherapy of each drug at its maximum dose, in patients with nondiabetic renal disease. Eleven percent of patients on combination treatment reached the combined primary endpoint of time to doubling of serum creatinine concentration or ESRD compared with 23% of patients on trandolapril alone (hazard ratio 0.38, 95% CI 0.18–0.63, P = 0.018) and 23% of those on losartan alone (hazard ratio 0.40, 95% CI 0.17–0.69, P = 0.016). Concurrent diuretic therapy will often be necessary in patients who already have renal insufficiency, because fluid overload is an important determinant of hypertension in this setting. If, after this step, target blood pressure and proteinuria are not achieved, the next antiproteinuric drug to be added is usually a nondihydropyridinic calcium-channel blocker. An abnormal lipid profile, besides accelerating atherosclerosis, can promote progression of renal disease. Thus, in patients with serum low-density lipoprotein (LDL) cholesterol >100 mg/dL, a statin may be added. Moreover, in those with diabetes glycemic, control is reinforced to achieve hemoglobin A1c <7.5%. Both lipid reduction and tight glycemic control are supposed to contribute to renoprotection. The multidrug approach to chronic nephropathies has been formalized in an intervention protocol that has been named “remission clinic” [35]. The protocol is targeted to blood pressure <120/80 mm Hg, proteinuria <0.3 g/24 h, LDL <100 mg/dL, LDL + very LDL <130 mg/dL, and hemoglobin A1c <7.5% (in patients with diabetes) (Fig. 3). The multiple drug approach has been tested in more than 40 patients in our unit, and we can show that this is feasible and effective.
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In looking for a more effective treatment, the role of lifestyle changes should not be overlooked. Smoking cessation per se may reduce disease progression by 30%, which qualifies it as the single most important renoprotective measure [36]. Physical activity has always been considered instrumental to the loss of excess weight, but it may have an intrinsic favorable effect, as documented by a small study in 20 patients with chronic kidney disease who were assigned to 12-week regular aquatic exercise or the armchair [37]. During this short period, the body mass index did not change in either group. However, proteinuria decreased by 50% in those who performed aquatic exercise, whereas it did not change in the sedentary group. The concept of a multidrug approach for renal disease is extraordinarily reminiscent of the recent proposal of Law et al [38] in the British Medical Journal to develop a single pill containing aspirin, a statin, 3 antihypertensive agents at half dose, and folic acid for the prevention of cardiovascular disease. The “super pill” could indeed be valuable, perhaps with some adjustments for patients with chronic nephropathies. One of the potential advantages of this “super pill” is that such an intervention could be made available also to patients in poor countries. RENOPROTECTION IN EMERGING COUNTRIES The problem that we are facing now is whether this approach is applicable to populations of middle- or lowincome countries. There are little and sparse data on the incidence and prevalence of chronic kidney disease in developing countries [39]. What is certain is that in all low-income countries there are no dialysis facilities, or not enough for all in need, and people still die of uremia. Simple and inexpensive screening programs are feasible at low cost in poor countries, and also simple and inexpensive treatments are plausible and possibly effective. The Kidney Help Trust of Chennai, India [40] has embarked on a screening program in an area of 25,000 people. Trained social and health workers recorded blood pressure and checked for abnormal glucose levels and for the presence of albumin in the urine. All those who were positive for high blood pressure, diabetes, or both were further studied and then treated with inexpensive antihypertensive and antidiabetic drugs. The cost of a 1year program has been 300,000 Indian rupees (US $6500 per year); per capita costs were US $0.30, well within the limit of Indian government per capita health expenditure of US $8. Excellent blood pressure control was achieved among patients with hypertension, whereas blood glucose control in patients with diabetes was considered good. Another experience of mass screening for kidney disease has been conducted, at very low cost, in Bolivia under the auspices of the International Society of Nephrology-Commission for the Global Advancement of
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Nephrology [41]. More than 14,000 people were screened for urinary abnormalities in 3 regions of Bolivia (urban, mountain, and forest areas) by social workers. Some of the patients who were found positive at first screening were then enrolled in a follow-up program. In Australia, a very successful program of detection and treatment of renal and cardiovascular diseases in Australian Aborigines has been conducted recently between 1995 and 2000 [42]. The treatment consisted of long-acting ACE inhibitors targeted to lower blood pressure. After an average of 3.4 years of follow-up, the incidence of ESRD was reduced by 63% and nonrenal death by 50%. From this study, it has been estimated that in 2 years this program may have saved from £800,000 to £4.1 million in the costs of dialysis avoided or delayed. Cost is the key factor to be considered here. A number of strategies, from discounted prices for medicine to softening of patent protection and drug donation, have been devised to increase the access to essential medicines where they are most needed [43]. Much current thinking about how to direct resources of richer countries for the benefit of the health of the developing world centers around government aid, tax incentives to encourage the pharmaceutical industry to tackle some of its problems, the mobilization of earmarked funds by nongovernment organizations, and hopes for further large donations from philanthropic bodies. Concern exists about the efficiency, bureaucracy and, above all, sustainability of many of these international sources of funding. An attractive novel model to overcome these shortcomings is—by analogy with the Global Fund to Fight AIDS, Tuberculosis and Malaria—to create a global fund for kidney diseases. This should be coordinated by the International Society of Nephrology-Commission for the Global Advancement of Nephrology and supported by resources made available yearly from different institutions and organizations. An important contribution should be provided by national nephrology societies of Western countries. Also, pharmaceutical companies may be asked to contribute support with donations to a global fund for kidney disease. The sales of antihypertensive drugs and especially ACE inhibitors have been very successful, and these drugs give big returns to their manufacturers; a donation of a small proportion of the overall revenues could be taken in consideration. The contribution by the industry to the fund for advancement of global health, even with only a small part of the profit, could be negotiated as a moral obligation. The implementation of such an ambitious program cannot be realized without the involvement of international agencies such as the World Health Organization and the World Bank. At the local level, it is important to establish contacts with national scientific societies. Such contacts are indispensable tools for health authorities and national governments.
It is true that money is hard to find and when available is always less than needed. However, the value of the investment in renal prevention programs is astonishing. Reprint requests to Giuseppe Remuzzi, M.D., F.R.C.P., Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo-Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy. E-mail: [email protected]
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antagonism on blood pressure and renin release in sodium-depleted normotensives. Circulation 92:825–834, 1995 RUSSO D, PISANI A, BALLETTA MM, et al: Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 33:851–856, 1999 NAKAO N, YOSHIMURA A, MORITA H, et al: Combination treatment of angiotensin-II receptor blocker and angiotensinconverting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomized controlled trial. Lancet 361:117–124, 2003 RUGGENENTI P, SCHIEPPATI A, REMUZZI G: Progression, remission, regression of chronic renal diseases. Lancet 357:1601–1608, 2001 ORTH SR, STOCKMANN A, CONRADT C, et al: Smoking as a risk factor for end-stage renal failure in men with primary renal disease. Kidney Int 54:926–931, 1998 PECHTER U, OTS M, MESIKEPP S, et al: Beneficial effects of waterbased exercise in patients with chronic kidney disease. Int J Rehabil Res 26:153–156, 2003 LAW MR, WALD NJ, MORRIS JK, JORDAN RE: Value of low dose combination treatment with blood pressure lowering drugs: Analysis of 354 randomized trials. BMJ 326:1427–1435, 2003 KHER V: End-stage renal disease in developing countries. Kidney Int 62:350–362, 2002 MANI MK: The management of end-stage renal disease in India. Artif Org 22:182–186, 1998 PLATA R, SILVA C, YAHUITA J, et al: The first clinical and epidemiological programme on renal disease in Bolivia: A model for prevention and early diagnosis of renal diseases in developing countries. Nephrol Dial Transplant 13:3034–3036, 1998 HOY WE, WANG Z, BAKER PR, KELLY AM: Secondary prevention of renal and cardiovascular disease: Results of a renal and cardiovascular treatment program in an Australian aboriginal community. J Am Soc Nephrol 14(Suppl 2):S178–185, 2003 HENRY D, LEXCHIN J: The pharmaceutical industry as a medicine provider. Lancet 369:1590–1595, 2002
The future of renoprotection NORBERTO PERICO, IGOR CODREANU, ARRIGO SCHIEPPATI, and GIUSEPPE REMUZZI Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo-Mario Negri Institute for Pharmacological Research, Bergamo, Italy; and Department of Hemodialysis and Kidney Transplantation, Republican Clinical Hospital, Chisinau, Moldova
cronica ´ (IRC) y en su mayor parte, proveen de una buena calidad de vida. En los pa´ıses desarrollados el numero ´ de pacientes nuevos en dialisis ´ sobrepasa al de los que fallecen, por lo que el numero ´ de pacientes en dialisis ´ va en aumento. Es motivo de preocupacion ´ el que la provision ´ de un tratamiento adecuado a todo aquel que lo necesita, este consumiendo un elevado porcentaje de los presupuestos destinados a la atencion ´ de la salud. Dado de que esta´ fuera de consideracion ´ el racionar o el decidir que pacientes no reciban tratamiento dial´ıtico, debemos de buscar las medidas necesarias que prevengan el uso de dialisis ´ en tantos pacientes como sea posible. Es factible y posible el utilizar tratamientos sencillos y de bajo costo. Existe una solida ´ evidencia experimental de que la proteinuria es responsable de la inflamacion ´ y subsiguiente fibrosis del intersticio renal, contribuyendo de esta forma al deterioro de la funcion ´ renal. Estudios cl´ınicos realizados en pacientes con nefropat´ıas progresivas, indican que las observaciones hechas en animales de experimentacion ´ son relevantes al estudio de la enfermedad en humanos. Se ha encontrado una importante correlacion ´ entre la proteinuria y la disminucion ´ en la velocidad de filtracion ´ glomerular, tanto en pacientes con nefropat´ıa diabetica ´ como no diabetica. ´ La renoproteccion ´ es una estrategia dirigida a interrumpir o revertir este proceso. El tratamiento actual de las nefropat´ıas cronicas ´ se basa en el concepto de que la utilizacion ´ del bloqueo del sistema renina angiotensina con inhibidores de la ECA y/o bloqueadores del receptor de la angiotensina, disminuye la proteinuria, la perdida de la filtracion ´ glomerular y el riesgo de IRC, en forma mas ´ efectiva que otros farmacos ´ antihipertensivos. Sin embargo, rara vez se obtiene una remision ´ total, especialmente si el tratamiento se inicia en forma tard´ıa. En individuos que no respondan a dicha terapia, se debe de utilizar una estrategia de proteccion ´ renal multiple. ´ Cambios en los habitos ´ de vida del individuo, incluyendo el abandono del tabaco, no deben de ser pasados por alto. Un abordaje concertado, multifactorial y estrategico, ´ sustentado por una solida ´ evidencia cient´ıfica, es indispensable para revertir el incremento en la incidencia de estas enfermedades cronicas, ´ no solo para el beneficio de unos cuantos, sino en una forma globaly equitativa.
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. Resumen Las enfermedades renales cronicas ´ se han constituido en una seria amenaza global a la salud. La dialisis ´ y el trasplante renal prolongan la vida de los pacientes con insuficiencia renal
THE BURDEN OF CHRONIC RENAL DISEASES Chronic kidney diseases are emerging as a global threat to human health [1]. During the last decade, the dialysis population has been growing at an average of 7% per year. There are now approximately 1.1 million people worldwide on renal replacement therapy (RRT) and, according to reliable estimates, the number of patients on maintenance dialysis will double in 10 years (Fig. 1). The
Key words: renoprotection, proteinuria, renin-angiotensin system blockade, chronic kidney disease. C
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2,095,000
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2000
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Fig. 1. Global maintenance dialysis population from 1990 to 2010 (modified from [2]).
total cumulative cost for RRT in the next decade will exceed US $1 trillion [2], a surprising figure from any point of view. In the United States, the total Medicare cost for dialysis and transplantation was US $12.7 billion in 1999 and is expected to exceed US $28.3 billion in 2010. Although this sum is 6% of the total Medicare budget, it serves only 0.7% of the Medicare population. In the European Union, the percentage of the health care expenditure absorbed by RRT programs ranges from 0.7% to 1.8%, whereas patients with end-stage renal disease (ESRD) are 0.025% to 0.06% of the total population. Continuing provision of adequate facilities, equipment, and manpower to assist the growing number of patients with ESRD will pose a substantial burden on health care resources in all developed countries in the near future. Thus, the cost and complexity of RRT put it out of reach for low-income countries, which are struggling to provide preventive and therapeutic measures for communicable diseases such as malaria, tuberculosis, acquired immune deficiency syndrome, and tropical disease infections, and have to assign their meager budget to sanitation, vaccine, nutrition, and other basic needs. Contemporary treatment for ESRD is so costly that there is little chance that the vast majority of the world’s population will have access to it. Less-privileged countries simply cannot establish programs for regular RRT for all patients with chronic kidney disease because of its prohibitive cost [3]. How might the global burden of chronic kidney disease be diminished in the future? At the present, there are no definitive cures for most acquired kidney diseases, and there is no reasonable expectation that gene therapy will be available soon enough to treat genetic forms of kidney diseases, such as polycystic kidney disease. Renal transplantation is limited by organ shortage [4], a worldwide problem that is not likely to be resolved by xenotransplantation in the near or immediate future. The best we can do at the present time is to concentrate our efforts on the prevention of progression of renal diseases.
MECHANISMS OF RENAL DISEASE PROGRESSION During the last 20 years, research in animals and people has helped our understanding of the mechanisms by which chronic kidney diseases progresses and has indicated possible preventive methods. A large number of studies established that progressive deterioration of renal function is the result of compensatory glomerular hemodynamic changes in response to nephron loss. In a widely used experimental model of renal mass reduction, the remaining nephrons undergo hypertrophy, reduced arteriolar resistance, and increased glomerular blood flow [5]. There is a lot of experimental and clinical evidence that pharmacologic inhibition of reninangiotensin system with angiotensin-converting enzyme (ACE) inhibitors or with angiotensin II subtype 1 receptor antagonists (ARB) slow the progression of renal failure. In vivo, angiotensin II enhances the vascular tone of both afferent and efferent glomerular arterioles and modulates intraglomerular capillary pressure and glomerular filtration rate (GFR) [6]. Aside from these glomerular hemodynamic effects of angiotensin II, other studies have revealed several nonhemodynamic effects of angiotensin II that may also be important. These findings have suggested that angiotensin II may alter permselective properties of the glomerular capillary barrier by mediating contraction of the foot processes, ultimately changing slit-diaphragm architecture and allowing proteins to escape more easily into the urinary space [7]. Abnormal protein trafficking through the glomerular capillary wall might contribute to progression of renal disease. Indeed, recent data are in support of the possibility that the excessive protein load of podocytes can be a factor underlying progressive injury of these glomerular cells and through their release of transforming growth factor b1, ultimately allowing myofibroblast differentiation of mesangial cells [8]. Moreover, excessive protein reabsorption by proximal tubuli provides further intrinsic toxicity to this nephron segment. Thus, both in vitro and in vivo, protein overload causes increased production of vasoactive and inflammatory mediators such as endothelin-1, monocyte chemoattractant protein-1, normal T cell expressed and secreted, a chemotactic cytokine for monocytes and memory T cells, and osteopontin [9]. The activation of a variety of molecules, such as cytokines, growth factors, and vasoactive substances, may result in abnormal accumulation of extracellular matrix collagen, fibronectin, and other components that are responsible for interstitial fibrosis. Proinflammatory mediators promote local recruitment of macrophages and lymphocytes [10], which, in turn, can stimulate the transformation of interstitial cells into myofibroblasts. Proximal tubular epithelial cells can interact with interstitial fibroblast to promote fibrogenesis via release of profibrogenic molecules [11].
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Glomerular -capillary hypertension
Increased glomerular permeability to macromolecules Increased filtration of plasma proteins
Proteinuria
Excessive tubular reabsorption Nuclear signals for NF-κB-dependent and independent vasoactive and inflammatory genes. Corresponding protein products then released into interstitium Tubular cell transdifferentiation
Fibroblast proliferation
Fibrogenesis Renal scarring
In summary, there is robust experimental evidence that proteinuria is responsible for interstitial inflammation and subsequent fibrosis, thereby contributing to progressive renal function loss (Fig. 2). THE CONCEPT OF RENOPROTECTION In chronic proteinuric nephropathies, if the interstitial inflammatory reaction and subsequent fibrosis were indeed a feature of protein overloading, limiting protein traffic or the biologic effect of excessive tubular protein reabsorption should prevent or slow progression of renal disease. This is precisely what happens in animals treated with ACE inhibitors. The experimental demonstration that the blockade of angiotensin II with ACE inhibitors slowed the progressive loss of renal function in a number of animal models of renal diseases, including diabetic nephropathy [12, 13], offered the opportunity, for the first time, to devise a treatment strategy that was not limited to passively accompanying patients to their destiny of dialysis; instead, it was aimed at preserving renal function as long as possible. The concept of renoprotection has thus emerged. The recent development of a new class of drugs, the angiotensin-receptor blockers (ARBs) has offered a further opportunity to improve renoprotection. The combination of 2 drugs, an ACE inhibitor and an ARB, in an experimental model of chronic nephropathy, was associated with a significant reduction of proteinuria and a trend toward less renal injury than with each drug alone [14]. The near-complete abolition of angiotensin II activity is instrumental to achieve full renal protection. Clinical studies and clinicopathologic correlations in patients with progressive nephropathies indicate that observations in
Fig. 2. Pathophysiology nephropathies.
of
progressive
experimental models are relevant to understanding human disease [15]. Researchers identified an important correlation between urinary protein excretion and rate of GFR decline in patients with diabetic [16] and nondiabetic chronic nephropathy [17]. The role of proteinuria as a strong, independent predictor of ESRD has been recently documented in a mass-screening setting [18]. By screening more than 100,000 healthy patients in 1983 in Okinawa, Japan, and following up with them for up to 17 years, a positive relationship was found between baseline proteinuria (by dipstick urine test) and the risk for developing ESRD. Even a slight increase in proteinuria was an independent risk factor for ESRD. Moreover, the predictive value of the protein excretion rate was independent of baseline GFR levels [19]. Whenever proteinuria is decreased, progression to ESRD is reduced [20–23]. Results of the Modification of Diet in Renal Disease study [20] established that a reduction of proteinuria was associated with a decrease in the rate of decline in GFR, and that 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 [23]. This study was designed to assess the hypothesis that ACE inhibition might be superior to other antihypertensive drugs in reducing proteinuria, limiting the decline in GFR, and preventing ESRD in patients with chronic nephropathies. In this study, patients were randomly assigned to receive ramipril or conventional antihypertensive therapy to maintain diastolic blood pressure at 90 mm Hg or less. A prestratification strategy recognized 2 levels of proteinuria (stratum 1: >1 and <3 g/24 h; stratum 2: =3 g/24
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Remission clinic Targets of the multidrug approach: Blood pressure
<120/80 mm Hg
Proteinuria
<0.3 g/24 h
LDL
<100 mg/dL
LDL + VLDL
<130 mg/dL
HbA1c
<75% (diabetics)
Lifestyle changes Stop smoking, exercise, lower salt, protein, and calories in diet, lose weight Fig. 3. Targets for the remission clinic for chronic nephropathies that can be achieved by multidrug approach and lifestyle changes.
h). The study showed that although blood pressure control was similar in the 2 treatment groups, ACE inhibitor therapy decreased the progression to ESRD by 50% [23, 24]. Patients who had more proteinuria to start with benefited more from blood-pressure–lowering treatment than those who had less proteinuria. A meta-analysis [25] in 1860 patients with chronic nephropathies also recorded that the benefit of ACE inhibition was greatest in patients with high urine protein excretion at baseline. This drug class seems to have a greater antiproteinuric effect than other antihypertensive drugs, despite equal effects on blood pressure; the investigators concluded that proteinuria is the most important modifiable risk factor to slow progression and that reduction of urine protein excretion is the main goal for treatment. The REIN study was continued for 2 years (the REIN follow-up study), during which all patients previously on placebo were switched to ACE inhibitor [24]. In patients who continued to receive ramipril, GFR further decreased to approximately 0.1 mL/min/month during follow-up, a figure similar to that associated with normal aging. Patients who switched from conventional therapy to ramipril also benefited from treatment. One of the most impressive findings of this prolonged follow-up was that after about 36 months of treatment with ramipril, no additional patients progressed to the point of requiring dialysis, whereas patients switched from conventional therapy to ramipril continued to develop ESRD. A breakpoint was sought in the individual GFR slopes of patients receiving continued ramipril therapy to further investigate the nature of time-dependent improvement in GFR change. It could be predicted that after the breakpoint, 10 patients receiving continued ramipril therapy would never progress to ESRD and that those 10 patients had such improved GFR slopes that progression to ESRD would be delayed by about 5 years. The analysis provides evidence that the
tendency of GFR to decline with time can be halted, and remission is achievable in some patients with chronic renal disease. The decade of large clinical trials in nephropathy was closed when the results of 3 important studies were published in the New England Journal of Medicine [26–28]. All 3 studies examined the role of ARBs in type 2 diabetic nephropathy. One study evaluated the renoprotective effect of the ARB irbesartan in patients with hypertension with incipient nephropathy [28]. The goal of the study was the time of onset of overt albuminuria. In 2 years’ followup, only 5.2% of patients receiving 300 mg of irbesartan reached that goal, as compared with 14.9% of patients on placebo. The groups had similar blood pressure control, a finding that suggests that ARBs are renoprotective independently of their antihypertensive effect. The role of ARB in overt diabetic nephropathy was explored in 2 other trials published in 2001 [26, 28]. In both studies, treatment with ARB resulted in a significant reduction of proteinuria, incidence of serum creatinine doubling, and risk of ESRD. Although we have limited our review to only a few clinical studies, several other trials have been published, some of them small, and with little statistical power and short follow-up. However, they all point in one direction: blockade of renin-angiotensin system is beneficial in most chronic nephropathies. This may not be true in overt nephropathy of type 2 diabetes. The results of several clinical trials have shown, with one exception, that no significant difference was found in terms of renoprotection, as measured as prevention of GFR decline over time, between ACE inhibitors and other antihypertensive agents [29]. Indeed, in patients with type 2 diabetic nephropathy, overt proteinuria, and renal insufficiency, an ACE inhibitor was not able to modify renal hemodynamics and glomerular-sieving properties, despite effective blood pressure control [30]. In summary, currently available treatments have uniformly shown that reduction of blood pressure per se is beneficial in patients with type 2 diabetic nephropathy, whereas the effect of renin-angiotensin system blockade is probably less relevant than in type 1 diabetic nephropathy or nondiabetic nephropathies. Nevertheless, the results of the last decade of experiments and trials provide an important platform of knowledge to devise the best strategy in preventing diabetic nephropathy in the next 10 years. WHAT DOES THE FUTURE HOLD FOR RENOPROTECTION? Evidence from clinical trials suggests that the current practice can, at best, postpone ESRD for a few years but will not allow patients to avoid dialysis during their lifetime. Nevertheless, significant reduction of the incidence of ESRD is likely to be achieved in the near future for
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nondiabetic 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 pharmacologic intervention. By analogy with other major medical diseases (e.g., cancer, human immunodeficiency virus, and organ transplantation), a multidrug intervention may be the strategy needed to significantly retard dialysis [31]. Experimental data in rat models support this notion [14]. On clinical grounds, there are a few trials that show that the combination of an ACE inhibitor with an ARB affords greater renoprotection than each drug used alone. Preliminary studies in sodium-depleted healthy volunteers and in patients with diabetes with normal renal function recorded greater reduction in blood pressure and greater increases in plasma renin activity after the addition of losartan to enalapril treatment than after doubling the dose of enalapril [32]. An additive antiproteinuric effect of ACE inhibition and angiotensin II receptor antagonism has been reported in normotensive patients with immunoglobulin A nephropathy; systemic blood pressure was not affected [33]. The COOPERATE study [34] compared a combined treatment of ACE inhibitor and angiotensin II receptor blocker, with monotherapy of each drug at its maximum dose, in patients with nondiabetic renal disease. Eleven percent of patients on combination treatment reached the combined primary endpoint of time to doubling of serum creatinine concentration or ESRD compared with 23% of patients on trandolapril alone (hazard ratio 0.38, 95% CI 0.18–0.63, P = 0.018) and 23% of those on losartan alone (hazard ratio 0.40, 95% CI 0.17–0.69, P = 0.016). Concurrent diuretic therapy will often be necessary in patients who already have renal insufficiency, because fluid overload is an important determinant of hypertension in this setting. If, after this step, target blood pressure and proteinuria are not achieved, the next antiproteinuric drug to be added is usually a nondihydropyridinic calcium-channel blocker. An abnormal lipid profile, besides accelerating atherosclerosis, can promote progression of renal disease. Thus, in patients with serum low-density lipoprotein (LDL) cholesterol >100 mg/dL, a statin may be added. Moreover, in those with diabetes glycemic, control is reinforced to achieve hemoglobin A1c <7.5%. Both lipid reduction and tight glycemic control are supposed to contribute to renoprotection. The multidrug approach to chronic nephropathies has been formalized in an intervention protocol that has been named “remission clinic” [35]. The protocol is targeted to blood pressure <120/80 mm Hg, proteinuria <0.3 g/24 h, LDL <100 mg/dL, LDL + very LDL <130 mg/dL, and hemoglobin A1c <7.5% (in patients with diabetes) (Fig. 3). The multiple drug approach has been tested in more than 40 patients in our unit, and we can show that this is feasible and effective.
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In looking for a more effective treatment, the role of lifestyle changes should not be overlooked. Smoking cessation per se may reduce disease progression by 30%, which qualifies it as the single most important renoprotective measure [36]. Physical activity has always been considered instrumental to the loss of excess weight, but it may have an intrinsic favorable effect, as documented by a small study in 20 patients with chronic kidney disease who were assigned to 12-week regular aquatic exercise or the armchair [37]. During this short period, the body mass index did not change in either group. However, proteinuria decreased by 50% in those who performed aquatic exercise, whereas it did not change in the sedentary group. The concept of a multidrug approach for renal disease is extraordinarily reminiscent of the recent proposal of Law et al [38] in the British Medical Journal to develop a single pill containing aspirin, a statin, 3 antihypertensive agents at half dose, and folic acid for the prevention of cardiovascular disease. The “super pill” could indeed be valuable, perhaps with some adjustments for patients with chronic nephropathies. One of the potential advantages of this “super pill” is that such an intervention could be made available also to patients in poor countries. RENOPROTECTION IN EMERGING COUNTRIES The problem that we are facing now is whether this approach is applicable to populations of middle- or lowincome countries. There are little and sparse data on the incidence and prevalence of chronic kidney disease in developing countries [39]. What is certain is that in all low-income countries there are no dialysis facilities, or not enough for all in need, and people still die of uremia. Simple and inexpensive screening programs are feasible at low cost in poor countries, and also simple and inexpensive treatments are plausible and possibly effective. The Kidney Help Trust of Chennai, India [40] has embarked on a screening program in an area of 25,000 people. Trained social and health workers recorded blood pressure and checked for abnormal glucose levels and for the presence of albumin in the urine. All those who were positive for high blood pressure, diabetes, or both were further studied and then treated with inexpensive antihypertensive and antidiabetic drugs. The cost of a 1year program has been 300,000 Indian rupees (US $6500 per year); per capita costs were US $0.30, well within the limit of Indian government per capita health expenditure of US $8. Excellent blood pressure control was achieved among patients with hypertension, whereas blood glucose control in patients with diabetes was considered good. Another experience of mass screening for kidney disease has been conducted, at very low cost, in Bolivia under the auspices of the International Society of Nephrology-Commission for the Global Advancement of
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Nephrology [41]. More than 14,000 people were screened for urinary abnormalities in 3 regions of Bolivia (urban, mountain, and forest areas) by social workers. Some of the patients who were found positive at first screening were then enrolled in a follow-up program. In Australia, a very successful program of detection and treatment of renal and cardiovascular diseases in Australian Aborigines has been conducted recently between 1995 and 2000 [42]. The treatment consisted of long-acting ACE inhibitors targeted to lower blood pressure. After an average of 3.4 years of follow-up, the incidence of ESRD was reduced by 63% and nonrenal death by 50%. From this study, it has been estimated that in 2 years this program may have saved from £800,000 to £4.1 million in the costs of dialysis avoided or delayed. Cost is the key factor to be considered here. A number of strategies, from discounted prices for medicine to softening of patent protection and drug donation, have been devised to increase the access to essential medicines where they are most needed [43]. Much current thinking about how to direct resources of richer countries for the benefit of the health of the developing world centers around government aid, tax incentives to encourage the pharmaceutical industry to tackle some of its problems, the mobilization of earmarked funds by nongovernment organizations, and hopes for further large donations from philanthropic bodies. Concern exists about the efficiency, bureaucracy and, above all, sustainability of many of these international sources of funding. An attractive novel model to overcome these shortcomings is—by analogy with the Global Fund to Fight AIDS, Tuberculosis and Malaria—to create a global fund for kidney diseases. This should be coordinated by the International Society of Nephrology-Commission for the Global Advancement of Nephrology and supported by resources made available yearly from different institutions and organizations. An important contribution should be provided by national nephrology societies of Western countries. Also, pharmaceutical companies may be asked to contribute support with donations to a global fund for kidney disease. The sales of antihypertensive drugs and especially ACE inhibitors have been very successful, and these drugs give big returns to their manufacturers; a donation of a small proportion of the overall revenues could be taken in consideration. The contribution by the industry to the fund for advancement of global health, even with only a small part of the profit, could be negotiated as a moral obligation. The implementation of such an ambitious program cannot be realized without the involvement of international agencies such as the World Health Organization and the World Bank. At the local level, it is important to establish contacts with national scientific societies. Such contacts are indispensable tools for health authorities and national governments.
It is true that money is hard to find and when available is always less than needed. However, the value of the investment in renal prevention programs is astonishing. Reprint requests to Giuseppe Remuzzi, M.D., F.R.C.P., Department of Medicine and Transplantation, Ospedali Riuniti di Bergamo-Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy. E-mail: [email protected]
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