Kidney International, Vol. 57, Suppl. 75 (2000), pp. S-71–S-76

Counteracting progression of renal disease:A look into the future

EBERHARD RITZ, MICHAEL SCHOMIG, and JURGEN WAGNER

Department of Internal Medicine, Ruperto Carola University, Heidelberg, Germany

Counteracting progression of renal disease: A look into the ence” or discontinuously via “scientific revolutions.” Ex-future. It is always risky to predict the future. It is the very amples of the latter include discoveries such as Schrod-nature of research, including medical research, that truly novel inger’s equations in quantum physics or the identificationresults are not predictable. Nevertheless, some predictions con-

of the double helix in biosciences. In all modesty, we willcerning the understanding and management of progression ofrenal disease are plausible. It is very likely that in the future, therefore have to restrict our considerations to “ordinaryexploding health budgets will force authorities and nephrolo- science,” the progress of which can reasonably be extrap-gists to more effectively apply existing knowledge in this field olated from what has been going on in the past. Byto patients with early renal disease, particularly diabetics. We

necessity, the much more exciting breaks in continuity,hope that this optimistic note is justified, although experienceadmittedly indicates that it is very much against human nature i.e., the “scientific revolutions,” will be beyond our abilityto behave rationally. With the powerful methodological tools to predict.available today, it is safe to predict that insight into the mecha- At the end of this century, it is instructive to considernisms underlying progression will also increase. Although phar-

what nephrology was like at the beginning of our century.macological blockade of the renin-angiotensin system has beenAt that time, even the term nephrology did not exist.one of the great success stories of the past two decades, in

many patients, progression is seen despite administration of To mention a few characteristic examples of the state ofangiotensin-converting enzyme (ACE) inhibitors and angio- renal disease at that time: Franz Volhard was just abouttensin receptor blockers. Fortunately, additional targets for

to propose a system of classification of glomerulonephri-intervention, such as endothelin-1, inflammatory cascades, che-tis, to distinguish benign and malignant hypertension,mokines, etc., are on the horizon. A particularly fertile target

for prevention of progression will be kidney grafts, since it and to postulate that a chemical factor is released byhas become increasingly clear that factors unrelated to allo- the kidney and causes vasoconstriction and malignantimmunity play an important role in chronic allograft nephrop-

hypertension. Renin, although discovered in 1897 by Ti-athy.gerstedt and Bergman, was still highly controversial, be-cause many investigators could not reproduce their re-sults. In vivo diffusion as a method designed to treatAt the end of the outgoing millennium, we have beendrug intoxication had just been introduced by Rowntreeasked to predict what will be the future of clinical ne-and Abel, but the potential for treating uremia was notphrology in the incoming millennium. There are numer-recognized, and the medical community had no inklingous examples of predictions that went wrong, such asof the ground-breaking future discoveries of Haas, Kolff,the advice given to Einstein by his school teacher not to

study physics because nothing new was left to discover and Scribner. In the first decade of the century, somein physics after Maxwell had found the electromagnetic crude attempts at kidney transplantation had been madefield equations. The prospect of such undoubted dangers in the absence of any knowledge of the immune barrier,of prediction is mitigated by the consideration that the but one could not have predicted even in his boldestreaders of this article presumably won’t live long enough dreams the ground-breaking discoveries of Murray andto be able to assess at the end of the millennium whether Hamburger. And, not to forget, at the beginning of thewe have been right or wrong. century, physicians had at their disposal next to no medi-

According to T.S. Kuhn, science proceeds in one of cation to treat renal disease. No one could foresee thetwo ways: either continuous progress by “ordinary sci- introduction of medication such as diuretics, antihyper-

tensive agents, and immunosuppressive drugs that haverevolutionized the treatment of renal disease. These con-Key words: renal failure, progression, glomerulosclerosis, interstitial

fibrosis, renal transplantation. siderations make one humble, and one wonders whetherour current management of renal disease will look any 2000 by the International Society of Nephrology

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Ritz et al: Counteracting progression of renal diseaseS-72

Table 2. Data on 173 diabetic patients at the time of admissionTable 1. Factors that increase the risk of progression toend-stage renal failure to a nephrologist

Age years 67 (31–95)Elevated blood pressureAlbuminuria or proteinuria Gender (male/female) 90 m/83 f

Diabetes type 16 type 1, 157 type 2Poor glycemic control (high level of insulin resistance)Smoking HbA1c % 7.9 (4.9–15.7)

Total cholesterol mg/dL 244 (88–521)High dietary intake of proteinsHyperlipidemia LDL-cholesterol mg/dL 170 (67–307)

Lipid-lowering therapy 8% of patientsMedian systolic blood pressure mm Hg 170 (120–260)Median diastolic blood pressure mm Hg 90 (60–180)No antihypertensive therapy 18% patientsACE inhibitors 52% patientsbetter to future nephrologists at the end of the nextBlood pressure self measurement 33% patients

century.Adapted from [1].

It is not unreasonable, however, to have high expecta-tions for the forthcoming century, let alone the millen-nium, because today investigators have at their disposalpowerful tools from molecular biology of drug modeling tion in Germany [3]. The DCCT trial in type 1 diabetesto sophisticated data handling. As a result the pace of [4] and the Kumamoto [5] and UK-PDS trials in type 2progress in life science has accelerated enormously. diabetes [6] clearly documented that near-normogly-Breakthroughs in methodology allow us to answer ques- cemia prevents microvascular complications in diabetictions that could not be solved previously. In particular, patients [7]. It is therefore sobering to see the quality ofrecent transfers of knowledge for other disciplines to glycemic control shown in Table 2, presumably even anrenal problems was most rewarding, and in the future the underestimate of the problem because glycemic controlinterdisciplinary approach will be even more important. tends to improve in preterminally uremic patients dueLeaving basic science alone, let us now consider, on a to anorexia and prolonged insulin half-life.more modest level, likely areas of progress in clinical The rate of admission of renal patients for renal re-nephrology concerning progression of renal disease, in placement therapy has continuously increased with moreparticular provision of renal care and better understand- frequent admission of elderly and of diabetic patients.ing of mechanisms involved in progression of primary The latter has been called a “medical catastrophe ofrenal disease and of allograft nephropathy. Better com- world-wide dimensions” [8] and this is illustrated by Ta-prehension of pathology will provide novel targets for ble 2. The rising incidence of end-stage renal failureprevention. in diabetics is scandalous because, at least in principle,

diabetic nephropathy is presumably a preventable condi-tion [9]. A further point is that progression can be attenu-

IMPROVED PROVISION OF RENAL CAREated, particularly when therapy is started early, as shown

Lord Rosenheim once stated that public health will by animal experiments that document diminished returnderive more benefit from applying what is known than in advanced stages.from waiting for scientific breakthroughs. Nowhere is The above findings indicate that so far nephrologiststhis statement more appropriate than for the provision have failed to “get the message across” to the medicalof renal care. Table 1 lists some risk factors for progres- and non-medical communities. Considerable efforts willsion of renal disease that are accessible to intervention, be required to achieve this goal. To this end one muste.g., blood pressure control, cessation of smoking, and (1) convince the general public of the importance of(in diabetic patients) near-normoglycemia. To what ex- prevention of renal disease, (2) to educate renal patientstent are these potential approaches implemented today? to be involved in, and be responsible for, their own care,A sobering answer is given by Table 2. In a retrospective and (3) to educate the non-nephrological medical com-analysis, we assessed the quality of nephrological care munity in order to make them aware of the recent revolu-in diabetic patients with renal disease at the time when tionary progress that has occurred in the prevention ofthey were admitted to a renal unit in Germany [1]. Me- renal disease. It is easy to predict that with the ageingdian admission systolic blood pressure was 170 mm Hg of the population and the rising prevalence of diabetes,(range 120–210) compared to the National Kidney Foun- the relative proportion of the health budget that willdation recommendation of 120/80 mm Hg. We and others have to go into renal care will increase. Although it isidentified smoking as a hitherto underappreciated risk very unusual for humans to behave rationally, one hopesfactor for progression of renal failure [2]. Nevertheless, that this unfortunate fact will heighten public awarenessamong patients admitted with an elevated serum creati- of renal problems and facilitate implementation of pre-nine concentration, 36% were smokers, compared to ventive measures in early stages of renal disease. To

what extent this strategy, designed for developed coun-39% in males and 37% in females of the general popula-

Ritz et al: Counteracting progression of renal disease S-73

tries, can also be applied in the developing world remains up that is familiar with it.” While there is ample evidencethat progression can be slowed down, we still need moreto be seen, but impressive evidence shows that even there

much can be achieved with relatively modest means [10]. definite information whether established renal failurecan be reversed.Recent progress into the genetic basis of renal risk

[11] will certainly not only provide insight into patho- Today we know that angiotensin II (Ang II) is a keyplayer in progression via hemodynamic and non-hemo-mechanisms, but will also provide a rational basis for

screening families of individuals with renal disease, given dynamic mechanisms. Undoubtedly introduction of ef-fective drugs for pharmacological blockade of the renin-the evidence of familial clustering primary renal disease

[12] or diabetes [13–15]. Even more exciting and relevant angiotensin system (RAS) was the single most importantinnovation in the treatment of progression.may be the identification and characterization of genes

which protect against progression. It appears paradoxical that blockade of the RAS is soeffective in diabetes mellitus, although the circulatingNowhere in internal medicine is the interpersonal rela-

tionship of the physician with his patient more important RAS is suppressed. This is presumably explained by highlocal intrarenal concentrations of RAS components asthan in our discipline, where we are dealing with chroni-

cally ill patients. Nephrologists are subject to enormous suggested by studies on the renal hemodynamic responseto ACE inhibition [22] and angiotensin receptor regula-financial pressures to rationalize their services, but much

attention is required, and will be required even more in tion [23]. Because of compartmentation of intrarenalangiotensin and the components of the RAS, it appearsthe future, to prevent renal care from being viewed from

a too-narrow, purely economic perspective. Progression plausible that the blood pressure response is a poor guideto the selection of the proper dose of ACE inhibitors.cannot only be viewed as a scientific or medical problem.

No good nephrologist is not aware that patients with Based on very sound animal experiments, it has beenpostulated that proteinuria per se is a “nephrotoxin”renal disease have fears, moments of despair and depres-

sion, for which they are in need of compassionate atten- [24]. It has also been proposed that one should increasethe dose of ACE inhibitors or angiotensin receptortion by empathetic physicians. The patient with progres-

sive renal failure is more than an organism with an blockers to the maximum that is tolerated [25, 26], basedon the observation that substantially higher doses ofincreasingly less efficient excretory apparatus.ACE inhibitors (or AT1-receptor blockers) than re-

Novel approaches to the prevention of progression of quired for lowering of blood pressure will further reducerenal disease the message of transforming growth factor-b (TGF-b),

one of the key players in progression.In this century it had been appreciated early on thatrenal failure may progress by non-specific mechanisms While this is certainly a sensible approach, we still see

patients in whom progression occurs despite maximal[16], and that blood pressure plays an important role inprogressive loss of renal function [17]. Nevertheless, it doses of ACE inhibitors (Fig. 1). This observation sug-

gests that, in addition to the RAS, other pathomechan-has been only after the recent introduction of novelmethodologies that the functional and molecular mecha- isms are also involved in the pathogenesis of progression.

One, certainly not the only, additional player in thisnisms underlying progression have been clarified to aconsiderable extent [18]. game appears to be endothelin (ET) [27–29].

In damaged kidneys, transcription of ET is increased.From a historical perspective, it is interesting that inthe 19th century, chronic “nephritis” was viewed as an Increased amounts of ET are excreted in the urine of

animals or patients with renal disease. In animal experi-interstitial process by Jacob Henle, a glomerular processby Theodor Frerichs, and a parenchymatous process by ments, non-selective and selective ET receptor antago-

nists effectively interfere with progression [27–29]. ThisRudolf Virchow. In retrospect, each of them was right toa certain extent, since recent investigators documented was seen in models of inflammatory and non-inflamma-

tory renal damage. Unfortunately, introduction of ETthat altered glomerular hemodynamics [19], activationof renal tubular epithelial cells [20] and interstitial fibro- receptor antagonists for renal pathology has been sur-

prisingly slow in coming, partly because of hepatotoxicitysis [21] all play a role in progression of renal disease. Itis also interesting to see how the focus of research and of early compounds and side effects seen with the newer

compounds. Nevertheless, on the basis of a priori reason-paradigms have shifted in this field, e.g. recently fromthe mesangial cell to the podocyte. It stands to reason ing, ET receptor blockade appears to be a very promising

therapeutic strategy. Because of marked interaction be-that we have learned meanwhile to dispassionately eval-uate scientific truth and to revise our paradigms, despite tween, and mutual reinforcement of, the RAS and the

ET systems, combination of RAS blockade and ET-the skeptical statement of Max Planck that “a new scien-tific truth does not triumph by convincing its opponents receptor blockade appears sensible [30].

Another interesting, novel approach includes sympa-and making them see the light, but rather because itsopponents eventually die, and a new generation grows thetic blockade. It has recently been documented that

Ritz et al: Counteracting progression of renal diseaseS-74

leading to self-perpetuating fibroblast activation. Thereseem to be final common pathways to fibrosis even whenthe process is initiated by non-inflammatory mecha-nisms, such as hypertension [34]. This process is associ-ated with cell activation and achieving cell quiescence isthe ultimate therapeutic goal. Whether a combinationof interventions to interfere with these inflammatorymechanisms and fibrogenesis on the one hand, with inter-ventions to block peptides such as Ang II or ET1, pro-vides additional benefit remains to be seen.

Because most of these mediators are pleiotropic, andbecause most of these systems are redundant, it willbe problematic to effectively block such pathways. Ingeneral, intervention at the level of early steps has beenquite successful (e.g. in the Thy1 model) [35], but thereal challenge is of course to interfere with the chronicphase of self-perpetuating progression [21]. What wedon’t know today is whether in this process there is apoint of no return.

What is at our disposal? Genetic manipulations, e.g.transfection, antisense strategies, etc., have so far yieldedlittle that promises to be applicable for clinical treatment.The role of intelligent novel approaches, e.g. aptamers[35], remains to be seen. What is the prediction for thefuture? The enormous amount of research and the rapididentification of the pathogenetic mechanisms involvedin progression cannot fail but to lead to introductionof new therapeutic agents. Undoubtedly, it would be atriumph of clinical nephrology if progression of renaldisease could be halted altogether, at least in the majorityof patients.Fig. 1. Time course of blood pressure, enalapril dose, proteinuria and

serum creatinine in a patient with membranous glomerulonephritis.

ALLOGRAFT NEPHROPATHY

There is no doubt that renal transplantation is theoptimal treatment of renal failure. While there has beennon-hypotensive doses of central sympathoplegic agents,considerable progress in improving the early results ofe.g. moxonidine [31] or beta blockers, interfere with pro-renal transplantation, chronic graft loss, as reflected bygression. These studies identify the sympathetic nerve

system as a potential therapeutic target. graft half-life, has not markedly improved in the pastthree decades. It is the current concept that chronic graftIt is also striking that renal functional prognosis is

considerably better in premenopausal women than in loss, in the past misleadingly designated “chronic rejec-tion,” is a complex process that is undoubtedly triggeredmen and postmenopausal women [32, 33]. In animal ex-

periments, androgens aggravate and (less convincingly) by an allo-immune response, causing endothelial cell dam-age and vasculitis as well as interstitial infiltration andestrogens mitigate renal disease. With the added ratio-

nale that estrogens presumably reduce the cardiovascu- interstitial nephritis. It has become obvious, however,that progression of this process is importantly modulatedlar risk, it remains to be investigated whether administra-

tion of estrogens, or some of the newer developments by non-allo-immune factors, such as blood pressure [36]and potentially also smoking, lipids, homocysteine, etc.of estrogen analogues, interfere with progression in post-

menopausal women. Because of the continuously expanding pool of pa-tients on renal replacement therapy in the future, it willGreat excitement has recently been generated by the

characterization of molecular mechanisms involved in be increasingly important to optimize the results of trans-plantation, and, to this end, preventing progression ofprogression, which can be viewed as a fibrogenic repair

mechanism gone awry causing activation of inflamma- allograft nephropathy will be an effective tool. Sincedeath with a functioning graft, mostly from cardiovascu-tory cascades, particularly of NF-kB, expression of che-

mokines, adhesion molecules, and a variety of signals lar causes, rivals allograft nephropathy as the cause of

Ritz et al: Counteracting progression of renal disease S-75

there is perhaps no better statement than what LudwigBuchner [42] wrote in his book in 1899 At the Death Bedof a Century:

He who believes in progress has no reason … to despair, but hemust not forget that progress … follows a zigzag line, so that hugeleaps of progress alternate with great steps backwards

This is an appropriately cautious note of optimism forthe forthcoming millennium as well.

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