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Counteracting progression of renal disease: A look into the future

2000; Elsevier BV; Volume: 57; Linguagem: Inglês

10.1046/j.1523-1755.2000.07513.x

1523-1755

Eberhard Ritz, Michael Schömig, Jürgen Wagner,

Blood Pressure and Hypertension Studies

Counteracting progression of renal disease: A look into the future. It is always risky to predict the future. It is the very nature of research, including medical research, that truly novel results are not predictable. Nevertheless, some predictions concerning the understanding and management of progression of renal disease are plausible. It is very likely that in the future, exploding health budgets will force authorities and nephrologists to more effectively apply existing knowledge in this field to patients with early renal disease, particularly diabetics. We hope that this optimistic note is justified, although experience admittedly indicates that it is very much against human nature to behave rationally. With the powerful methodological tools available today, it is safe to predict that insight into the mechanisms underlying progression will also increase. Although pharmacological blockade of the renin-angiotensin system has been one of the great success stories of the past two decades, in many patients, progression is seen despite administration of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers. Fortunately, additional targets for intervention, such as endothelin-1, inflammatory cascades, chemokines, etc., are on the horizon. A particularly fertile target for prevention of progression will be kidney grafts, since it has become increasingly clear that factors unrelated to allo-immunity play an important role in chronic allograft nephropathy. Counteracting progression of renal disease: A look into the future. It is always risky to predict the future. It is the very nature of research, including medical research, that truly novel results are not predictable. Nevertheless, some predictions concerning the understanding and management of progression of renal disease are plausible. It is very likely that in the future, exploding health budgets will force authorities and nephrologists to more effectively apply existing knowledge in this field to patients with early renal disease, particularly diabetics. We hope that this optimistic note is justified, although experience admittedly indicates that it is very much against human nature to behave rationally. With the powerful methodological tools available today, it is safe to predict that insight into the mechanisms underlying progression will also increase. Although pharmacological blockade of the renin-angiotensin system has been one of the great success stories of the past two decades, in many patients, progression is seen despite administration of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers. Fortunately, additional targets for intervention, such as endothelin-1, inflammatory cascades, chemokines, etc., are on the horizon. A particularly fertile target for prevention of progression will be kidney grafts, since it has become increasingly clear that factors unrelated to allo-immunity play an important role in chronic allograft nephropathy. At the end of the outgoing millennium, we have been asked to predict what will be the future of clinical nephrology in the incoming millennium. There are numerous examples of predictions that went wrong, such as the advice given to Einstein by his school teacher not to study physics because nothing new was left to discover in physics after Maxwell had found the electromagnetic field equations. The prospect of such undoubted dangers of prediction is mitigated by the consideration that the readers of this article presumably won't live long enough to be able to assess at the end of the millennium whether we have been right or wrong. According to T.S. Kuhn, science proceeds in one of two ways: either continuous progress by "ordinary science" or discontinuously via "scientific revolutions." Examples of the latter include discoveries such as Schrödinger's equations in quantum physics or the identification of the double helix in biosciences. In all modesty, we will therefore have to restrict our considerations to "ordinary science," the progress of which can reasonably be extrapolated from what has been going on in the past. By necessity, the much more exciting breaks in continuity, i.e., the "scientific revolutions," will be beyond our ability to predict. At the end of this century, it is instructive to consider what nephrology was like at the beginning of our century. At that time, even the term nephrology did not exist. To mention a few characteristic examples of the state of renal disease at that time: Franz Volhard was just about to propose a system of classification of glomerulonephritis, to distinguish benign and malignant hypertension, and to postulate that a chemical factor is released by the kidney and causes vasoconstriction and malignant hypertension. Renin, although discovered in 1897 by Tigerstedt and Bergman, was still highly controversial, because many investigators could not reproduce their results. In vivo diffusion as a method designed to treat drug intoxication had just been introduced by Rowntree and Abel, but the potential for treating uremia was not recognized, and the medical community had no inkling of the ground-breaking future discoveries of Haas, Kolff, and Scribner. In the first decade of the century, some crude attempts at kidney transplantation had been made in the absence of any knowledge of the immune barrier, but one could not have predicted even in his boldest dreams the ground-breaking discoveries of Murray and Hamburger. And, not to forget, at the beginning of the century, physicians had at their disposal next to no medication to treat renal disease. No one could foresee the introduction of medication such as diuretics, antihypertensive agents, and immunosuppressive drugs that have revolutionized the treatment of renal disease. These considerations make one humble, and one wonders whether our current management of renal disease will look any better to future nephrologists at the end of the next century. It is not unreasonable, however, to have high expectations for the forthcoming century, let alone the millennium, because today investigators have at their disposal powerful tools from molecular biology of drug modeling to sophisticated data handling. As a result the pace of progress in life science has accelerated enormously. Breakthroughs in methodology allow us to answer questions that could not be solved previously. In particular, recent transfers of knowledge for other disciplines to renal problems was most rewarding, and in the future the interdisciplinary approach will be even more important. Leaving basic science alone, let us now consider, on a more modest level, likely areas of progress in clinical nephrology concerning progression of renal disease, in particular provision of renal care and better understanding of mechanisms involved in progression of primary renal disease and of allograft nephropathy. Better comprehension of pathology will provide novel targets for prevention. Lord Rosenheim once stated that public health will derive more benefit from applying what is known than from waiting for scientific breakthroughs. Nowhere is this statement more appropriate than for the provision of renal care. Table 1 lists some risk factors for progression of renal disease that are accessible to intervention, e.g., blood pressure control, cessation of smoking, and (in diabetic patients) near-normoglycemia. To what extent are these potential approaches implemented today? A sobering answer is given by Table 2. In a retrospective analysis, we assessed the quality of nephrological care in diabetic patients with renal disease at the time when they were admitted to a renal unit in Germany1Keller C, Ritz E, Pommer W, Stein G, Frank J, Schwarzbeck A: Behandlungsqualita tniereninsuffizienter Diabetiker in Deutschland. Dtsch Med Wochenschr, in pressGoogle Scholar. Median admission systolic blood pressure was 170 mm Hg (range 120–210) compared to the National Kidney Foundation recommendation of 120/80 mm Hg. We and others identified smoking as a hitherto underappreciated risk factor for progression of renal failure2Orth S.R. Ritz E. Schrier R.W. The renal risk of smoking.Kidney Int. 1997; 51: 1669-1677Abstract Full Text PDF PubMed Scopus (213) Google Scholar. Nevertheless, among patients admitted with an elevated serum creatinine concentration, 36% were smokers, compared to 39% in males and 37% in females of the general population in Germany3Hüllinghorst R. Jahrbuch Sucht. Ed. Neuland Verlag, Geesthacht1996Google Scholar. The DCCT trial in type 1 diabetes4The Diabetes Control and Complications Trials Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N Engl J Med. 1993; 329: 977-986Crossref PubMed Scopus (22715) Google Scholar and the Kumamoto5Ohkubo Y. Kishikawa H. Araki E. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6 year study.Diabetes Res. 1995; 28: 103-117Scopus (2838) Google Scholar and UK-PDS trials in type 2 diabetes6UK Prospective Diabetes Study (UKPDS) Group Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes.Lancet. 1998; 352: 837-853Abstract Full Text Full Text PDF PubMed Scopus (18953) Google Scholar clearly documented that near-normoglycemia prevents microvascular complications in diabetic patients7Ismail N. Becker B. Strzelczyk P. Ritz E. Renal disease and hypertension in non-insulin-dependent diabetes mellitus.Kidney Int. 1999; 55: 1-28Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar. It is therefore sobering to see the quality of glycemic control shown in Table 2, presumably even an underestimate of the problem because glycemic control tends to improve in preterminally uremic patients due to anorexia and prolonged insulin half-life.Table 1Factors that increase the risk of progression to end-stage renal failureElevated blood pressureAlbuminuria or proteinuriaPoor glycemic control (high level of insulin resistance)SmokingHigh dietary intake of proteinsHyperlipidemia Open table in a new tab Table 2Data on 173 diabetic patients at the time of admission to a nephrologistAdapted from1Keller C, Ritz E, Pommer W, Stein G, Frank J, Schwarzbeck A: Behandlungsqualita tniereninsuffizienter Diabetiker in Deutschland. Dtsch Med Wochenschr, in pressGoogle Scholar.Age years67 (31–95)Gender (male/female)90 m/83 fDiabetes type16 type 1, 157 type 2HbA1c %7.9 (4.9–15.7)Total cholesterol mg/dL244 (88–521)LDL-cholesterol mg/dL170 (67–307)Lipid-lowering therapy8% of patientsMedian systolic blood pressure mm Hg170 (120–260)Median diastolic blood pressure mm Hg90 (60–180)No antihypertensive therapy18% patientsACE inhibitors52% patientsBlood pressure self measurement33% patients Open table in a new tab The rate of admission of renal patients for renal replacement therapy has continuously increased with more frequent admission of elderly and of diabetic patients. The latter has been called a "medical catastrophe of world-wide dimensions"8Ritz E. Rychlik I. Locatelli F. Halimi S. End-stage renal failure in type 2 diabetes: A medical catastrophe of worldwide dimensions.Am J Kidney Dis. 1999; 34: 795-808Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar and this is illustrated by Table 2. The rising incidence of end-stage renal failure in diabetics is scandalous because, at least in principle, diabetic nephropathy is presumably a preventable condition9Ritz E. Orth S.R. Nephropathy in patients with type 2 diabetes mellitus.N Engl J Med. 1999; 341: 1127-1133Crossref PubMed Scopus (657) Google Scholar. A further point is that progression can be attenuated, particularly when therapy is started early, as shown by animal experiments that document diminished return in advanced stages. The above findings indicate that so far nephrologists have failed to "get the message across" to the medical and non-medical communities. Considerable efforts will be required to achieve this goal. To this end one must (1) convince the general public of the importance of prevention of renal disease, (2) to educate renal patients to be involved in, and be responsible for, their own care, and (3) to educate the non-nephrological medical community in order to make them aware of the recent revolutionary progress that has occurred in the prevention of renal disease. It is easy to predict that with the ageing of the population and the rising prevalence of diabetes, the relative proportion of the health budget that will have to go into renal care will increase. Although it is very unusual for humans to behave rationally, one hopes that this unfortunate fact will heighten public awareness of renal problems and facilitate implementation of preventive measures in early stages of renal disease. To what extent this strategy, designed for developed countries, can also be applied in the developing world remains to be seen, but impressive evidence shows that even there much can be achieved with relatively modest means10Plata R. Silva C. Yahuita J. Perez L. Schieppati A. Remuzzi G. The first clinical and epidemiological programme on renal disease in Bolivia: a model for prevention and early diagnosis of renal diseases in the developing countries.Nephrol Dial Transplant. 1998; 13: 3034-3036Crossref PubMed Scopus (42) Google Scholar. Recent progress into the genetic basis of renal risk11Brown D.M. Provoost A.P. Dely M.J. Lander E.S. Jacob H.T. Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat.Nat Genet. 1996; 12: 44-51Crossref Scopus (235) Google Scholar will certainly not only provide insight into pathomechanisms, but will also provide a rational basis for screening families of individuals with renal disease, given the evidence of familial clustering primary renal disease12Rambausek M. Hartz G. Waldherr R. Andrassy K. Ritz E. Familial glomerulonephritis.Pediatr Nephrol. 1987; 1: 416-418Crossref PubMed Scopus (25) Google Scholar or diabetes13Seaquist E.R. Gotz F.C. Rich S. Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy.N Engl J Med. 1989; 320: 1161-1165Crossref PubMed Scopus (907) Google Scholar, 14Pettitt K.F. Saad M.F. Bennett P.H. Nelson R.G. Knowler W.C. Familial predisposition to renal disease in two generation of Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus.Diabetologia. 1990; 33: 438-442Crossref PubMed Scopus (372) Google Scholar, 15Strojek K. Grzeszczak W. Morawin E. Adamski M. Lacka B. Rudzki H. Ritz E. Nephropathy of type 2 diabetes: evidence for hereditary factors?.Kidney Int. 1997; 51: 1602-1607Abstract Full Text PDF PubMed Scopus (59) Google Scholar. Even more exciting and relevant may be the identification and characterization of genes which protect against progression. Nowhere in internal medicine is the interpersonal relationship of the physician with his patient more important than in our discipline, where we are dealing with chronically ill patients. Nephrologists are subject to enormous financial pressures to rationalize their services, but much attention is required, and will be required even more in the future, to prevent renal care from being viewed from a too-narrow, purely economic perspective. Progression cannot only be viewed as a scientific or medical problem. No good nephrologist is not aware that patients with renal disease have fears, moments of despair and depression, for which they are in need of compassionate attention by empathetic physicians. The patient with progressive renal failure is more than an organism with an increasingly less efficient excretory apparatus. In this century it had been appreciated early on that renal failure may progress by non-specific mechanisms16Smadel J.E. Experimental nephritis in rats induced by injection of anti-kidney serum.J Exp Med. 1939; 65: 541-555Crossref Scopus (10) Google Scholar, and that blood pressure plays an important role in progressive loss of renal function17Volhard F. Die doppelseitigen hämatogenen Nierenerkrankungen.Handbuch der Inneren Medizin. edited by Bergmann G, Staehelin R. Julius Springer, Berlin1931Google Scholar. Nevertheless, it has been only after the recent introduction of novel methodologies that the functional and molecular mechanisms underlying progression have been clarified to a considerable extent18Brenner B.M. Meyer T.W. Hostetter T.H. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular scleroses in aging, renal ablation, and intrinsic renal disease.N Engl J Med. 1982; 307: 652-659Crossref PubMed Scopus (145) Google Scholar. From a historical perspective, it is interesting that in the 19th century, chronic "nephritis" was viewed as an interstitial process by Jacob Henle, a glomerular process by Theodor Frerichs, and a parenchymatous process by Rudolf Virchow. In retrospect, each of them was right to a certain extent, since recent investigators documented that altered glomerular hemodynamics19Hostetter T.H. Olson J.L. Rennke H.G. Venkatachalam M.A. Brenner B.M. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation.Am J Physiol. 1981; 241: 85-93PubMed Google Scholar, activation of renal tubular epithelial cells20Remuzzi G. Bertani T. Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules?.Kidney Int. 1990; 38: 384-394Abstract Full Text PDF PubMed Scopus (381) Google Scholar and interstitial fibrosis21Müller G.A. Schettler V. Müller C.A. Strutz F. Prevention of progression of renal fibrosis: how far are we?.Kidney Int. 1996; 49: S-75-S-82Google Scholar all play a role in progression of renal disease. It is also interesting to see how the focus of research and paradigms have shifted in this field, e.g. recently from the mesangial cell to the podocyte. It stands to reason that we have learned meanwhile to dispassionately evaluate scientific truth and to revise our paradigms, despite the skeptical statement of Max Planck that "a new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it." While there is ample evidence that progression can be slowed down, we still need more definite information whether established renal failure can be reversed. Today we know that angiotensin II (Ang II) is a key player in progression via hemodynamic and non-hemodynamic mechanisms. Undoubtedly introduction of effective drugs for pharmacological blockade of the renin-angiotensin system (RAS) was the single most important innovation in the treatment of progression. It appears paradoxical that blockade of the RAS is so effective in diabetes mellitus, although the circulating RAS is suppressed. This is presumably explained by high local intrarenal concentrations of RAS components as suggested by studies on the renal hemodynamic response to ACE inhibition22Price D. Porter L.E. Gordon M. Fisher N.D.L. De'oliveira J.M.F. Laffel L.M.B. Passan D.R. Williams G.H. Hollenberg N.K. The paradox of the low-renin state in diabetic nephropathy.J Am Soc Nephrol. 1999; 10: 2382-2391PubMed Google Scholar and angiotensin receptor regulation23Wagner J. Gehlen F. Ciechanowicz A. Ritz E. Angiotensin II receptor type 1 gene expression in human glomerulonephritis and diabetes mellitus.J Am Soc Nephrol. 1999; 10: 545-551PubMed Google Scholar. Because of compartmentation of intrarenal angiotensin and the components of the RAS, it appears plausible that the blood pressure response is a poor guide to the selection of the proper dose of ACE inhibitors. Based on very sound animal experiments, it has been postulated that proteinuria per se is a "nephrotoxin"24Remuzzi G. Bertani T. Pathophysiology of progressive nephropathies.N Engl J Med. 1998; 339: 1448-1456Crossref PubMed Scopus (1150) Google Scholar. It has also been proposed that one should increase the dose of ACE inhibitors or angiotensin receptor blockers to the maximum that is tolerated25Peters H. Noble N.A. Border W.A. Targeting TGF-beta over-expression in renal disease: maximizing the antifibrotic action of angiotensin II blockade.Kidney Int. 1998; 54: 1575-1583Abstract Full Text Full Text PDF Scopus (223) Google Scholar,26Peters H. Ritz E. Dosing angiotensin II blockers—Beyond blood pressure.Nephrol Dial Transplant. 1999; 14: 2568-2570Crossref PubMed Scopus (28) Google Scholar, based on the observation that substantially higher doses of ACE inhibitors (or AT1-receptor blockers) than required for lowering of blood pressure will further reduce the message of transforming growth factor-β (TGF-β), one of the key players in progression. While this is certainly a sensible approach, we still see patients in whom progression occurs despite maximal doses of ACE inhibitors Figure 1. This observation suggests that, in addition to the RAS, other pathomechanisms are also involved in the pathogenesis of progression. One, certainly not the only, additional player in this game appears to be endothelin (ET)27Benigni A. Zoja C. Corna D. Orisio S. Longaretti L. Bertani T. Remuzzi G. A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression.Kidney Int. 1993; 44: 440-444Abstract Full Text PDF PubMed Scopus (229) Google Scholar, 28Nabakov A. Amann K. Wagner J. Gehlen F. Münter K. Ritz E. Influence of specific and non-specific endothelin receptor antagonists on renal morphology in rats with surgical renal ablation.Nephrol Dial Transplant. 1996; 11: 514-520Crossref Google Scholar, 29Orth S.R. Odoni G. Amann K. Strzelczyk P. Raschack M. Ritz E. The ET(A) receptor blocker LU 135252 prevents chronic transplant nephropathy in the "Fisher to Lewis" model.J Am Soc Nephrol. 1999; 10: 387-391PubMed Google Scholar. In damaged kidneys, transcription of ET is increased. Increased amounts of ET are excreted in the urine of animals or patients with renal disease. In animal experiments, non-selective and selective ET receptor antagonists effectively interfere with progression27Benigni A. Zoja C. Corna D. Orisio S. Longaretti L. Bertani T. Remuzzi G. A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression.Kidney Int. 1993; 44: 440-444Abstract Full Text PDF PubMed Scopus (229) Google Scholar, 28Nabakov A. Amann K. Wagner J. Gehlen F. Münter K. Ritz E. Influence of specific and non-specific endothelin receptor antagonists on renal morphology in rats with surgical renal ablation.Nephrol Dial Transplant. 1996; 11: 514-520Crossref Google Scholar, 29Orth S.R. Odoni G. Amann K. Strzelczyk P. Raschack M. Ritz E. The ET(A) receptor blocker LU 135252 prevents chronic transplant nephropathy in the "Fisher to Lewis" model.J Am Soc Nephrol. 1999; 10: 387-391PubMed Google Scholar. This was seen in models of inflammatory and non-inflammatory renal damage. Unfortunately, introduction of ET receptor antagonists for renal pathology has been surprisingly slow in coming, partly because of hepatotoxicity of early compounds and side effects seen with the newer compounds. Nevertheless, on the basis of a priori reasoning, ET receptor blockade appears to be a very promising therapeutic strategy. Because of marked interaction between, and mutual reinforcement of, the RAS and the ET systems, combination of RAS blockade and ET-receptor blockade appears sensible30Benigni A. Remuzzi G. Novel strategies to retard renal disease progression: combining ACE inhibition with endothelin receptor blocking?.Nephrol Dial Transplant. 1998; 13: 2734-2738Crossref Scopus (10) Google Scholar. Another interesting, novel approach includes sympathetic blockade. It has recently been documented that non-hypotensive doses of central sympathoplegic agents, e.g. moxonidine31Amann K, Rump LC, Simonaviciene A, Oberhauser V, Wessels S, Orth SR, Gross ML, Bielenberg GW, van Kats JP, Ehmke H,MallG,RitzE:Effects of sympathetic inhibition on glomerulo- sclerosis and albuminuria in subtotally nephrectomized rats. J Am Soc Nephrol, in press.Google Scholar or beta blockers, interfere with progression. These studies identify the sympathetic nerve system as a potential therapeutic target. It is also striking that renal functional prognosis is considerably better in premenopausal women than in men and postmenopausal women32Coggins C.H. Breyer Lewis J. Caggiula A.W. Castaldo L.S. Klahr S. Wang S.R. Differences between women and men with chronic renal disease.Nephrol Dial Transplant. 1998; 13: 1430-1437Crossref PubMed Scopus (118) Google Scholar,33Zeier M. Gafter U. Ritz E. Renal function and renal disease in males or females—Vive la petite difference.Nephrol Dial Transplant. 1998; 13: 2195-2198Crossref PubMed Scopus (22) Google Scholar. In animal experiments, androgens aggravate and (less convincingly) estrogens mitigate renal disease. With the added rationale that estrogens presumably reduce the cardiovascular risk, it remains to be investigated whether administration of estrogens, or some of the newer developments of estrogen analogues, interfere with progression in postmenopausal women. Great excitement has recently been generated by the characterization of molecular mechanisms involved in progression, which can be viewed as a fibrogenic repair mechanism gone awry causing activation of inflammatory cascades, particularly of NF-κB, expression of chemokines, adhesion molecules, and a variety of signals leading to self-perpetuating fibroblast activation. There seem to be final common pathways to fibrosis even when the process is initiated by non-inflammatory mechanisms, such as hypertension34Mervaala E.M. Müller D.N. Park J.K. Schmidt F. Lohn M. Breu V. Dragun D. Ganten D. Haller H. Luft F.C. Monocyte infiltration and adhesion molecules in a rat model of high human renin hypertension.Hypertension. 1999; 33: 389-395Crossref PubMed Google Scholar. This process is associated with cell activation and achieving cell quiescence is the ultimate therapeutic goal. Whether a combination of interventions to interfere with these inflammatory mechanisms and fibrogenesis on the one hand, with interventions to block peptides such as Ang II or ET1, provides additional benefit remains to be seen. Because most of these mediators are pleiotropic, and because most of these systems are redundant, it will be problematic to effectively block such pathways. In general, intervention at the level of early steps has been quite successful (e.g. in the Thy1 model)35Floege J. Ostendorf T. Janjié N. Aptamers: Novel tools for specific intervention studies.Nephrol Dial Transplant. 1999; 14: 1354-1357Crossref Scopus (3) Google Scholar, but the real challenge is of course to interfere with the chronic phase of self-perpetuating progression21Müller G.A. Schettler V. Müller C.A. Strutz F. Prevention of progression of renal fibrosis: how far are we?.Kidney Int. 1996; 49: S-75-S-82Google Scholar. What we don't know today is whether in this process there is a point of no return. What is at our disposal? Genetic manipulations, e.g. transfection, antisense strategies, etc., have so far yielded little that promises to be applicable for clinical treatment. The role of intelligent novel approaches, e.g. aptamers35Floege J. Ostendorf T. Janjié N. Aptamers: Novel tools for specific intervention studies.Nephrol Dial Transplant. 1999; 14: 1354-1357Crossref Scopus (3) Google Scholar, remains to be seen. What is the prediction for the future? The enormous amount of research and the rapid identification of the pathogenetic mechanisms involved in progression cannot fail but to lead to introduction of new therapeutic agents. Undoubtedly, it would be a triumph of clinical nephrology if progression of renal disease could be halted altogether, at least in the majority of patients. There is no doubt that renal transplantation is the optimal treatment of renal failure. While there has been considerable progress in improving the early results of renal transplantation, chronic graft loss, as reflected by graft half-life, has not markedly improved in the past three decades. It is the current concept that chronic graft loss, in the past misleadingly designated "chronic rejection," is a complex process that is undoubtedly triggered by an allo-immune response, causing endothelial cell damage and vasculitis as well as interstitial infiltration and interstitial nephritis. It has become obvious, however, that progression of this process is importantly modulated by non-allo-immune factors, such as blood pressure36Opelz G. Wujciak T. Ritz E. Association of chronic kidney graft failure with recipient blood pressure.Kidney Int. 1998; 53: 217-222Abstract Full Text PDF PubMed Scopus (550) Google Scholar and potentially also smoking, lipids, homocysteine, etc. Because of the continuously expanding pool of patients on renal replacement therapy in the future, it will be increasingly important to optimize the results of transplantation, and, to this end, preventing progression of allograft nephropathy will be an effective tool. Since death with a functioning graft, mostly from cardiovascular causes, rivals allograft nephropathy as the cause of graft loss37Lindholm A. Albrechtsen D. Frödin L. Tufveson G. Persson N.H. Lundgren G. Ischemic heart disease—Major cause of death and graft loss after renal transplantation in Scandinavia.Transplantation. 1995; 60: 451-457Crossref PubMed Scopus (329) Google Scholar, preventing cardiovascular death will be a very effective means of improving the results of transplantation as well. Fortunately, the strategies for reducing allograft nephropathy and for reducing cardiovascular death are very similar. As shown in Figure 2, blood pressure is an important determinant of graft loss. There are good indirect arguments that this relationship is causal. Superimposition of blood pressure on chronic rejection, e.g. in the Fisher to Lewis model, accelerates graft damage and graft loss. In grafted patients with vascular rejection, blood pressure is also an important determinant of graft loss38Cosio F.G. Pelletier R.P. Sedmak D.D. Peavento T.E. Henry M.L. Ferguson R.M. Renal allograft survival following acute rejection correlates with blood pressure levels and histopathology.Kidney Int. 1999; 56: 1912-1919Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar. There is good evidence that Ang II might be involved in the genesis of the vascular lesions. In animal experiments, Michel39Mourlon-Le Grand M.C. Poitevin P. Benessiano J. Duriez M. Michel J.B. Levy B.I. Effect of a nonhypotensive long-term infusion of ANP on the mechanical and structural properties of the arterial wall in Wistar-Kyoto and spontaneously hypertensive rats.Arterioscl Thromb. 1993; 13: 640-650Crossref PubMed Google Scholar noted that ACE inhibitors reduced intima proliferation, while lesions in the media were scarcely affected. ACE inhibitors also reduce proteinuria40Hausberg M. Barenbrock M. Hohage H. Müller S. Heidenreich S. Rahn K.H. ACE inhibitor versus beta-blocker for the treatment of hypertension in renal allograft recipients.Hypertension. 1999; 33: 862-868Crossref PubMed Scopus (80) Google Scholar, presumably by interfering with glomerular injury, an important player is graft dysfunction. Thus, lowering blood pressure to rigid target pressure levels and particularly use of ACE inhibitors will be important clinical tools in the future. We have recently summarized the evidence that smoking accelerates loss of renal function in patients with primary renal disease2Orth S.R. Ritz E. Schrier R.W. The renal risk of smoking.Kidney Int. 1997; 51: 1669-1677Abstract Full Text PDF PubMed Scopus (213) Google Scholar and preliminary data of our group suggest that the same is true for allografts. We shall not discuss in detail factors such as lipids, particularly oxidized lipids, homocysteine concentrations, and others, that presumably also contribute to progression of allograft nephropathy41Fellström B. Backman U. Larsson E. Zezina L. Immunologic and nonimmunologic risk factors of chronic rejection.Transplant Proc. 1993; 31: 1304-1305Abstract Full Text Full Text PDF Scopus (12) Google Scholar. From all these considerations, one can conclude that the expertise of the clinical nephrologists will be increasingly in demand in the management of the patient with renal graft if these aspects are to be properly taken care of. To sum up our expectations: At the end of our century there is perhaps no better statement than what Ludwig Büchner42Büchner L. Am Sterbelager des Jahrhunderts. Blicke eines freien Denkers aus der Zeit in die Zeit. Gießen, Roth1900Google Scholar wrote in his book in 1899 At the Death Bed of a Century: He who believes in progress has no reason … to despair, but he must not forget that progress … follows a zigzag line, so that huge leaps of progress alternate with great steps backwards This is an appropriately cautious note of optimism for the forthcoming millennium as well.