These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly.ORIGINAL ARTICLE How Can We Improve Prognosis in Diabetic Patients With End-Stage Renal Disease? Eberhard Ritz, MD Diabetes has become the single most important cause of end-stage renal failure, but survival of diabetic patients with renal replacement therapy continues to be poor. The major causes of death are cardiovascular complications. Most cardiovascular complications, particularly coronary atheroma, accumulate before patients enter renal replacement programs. This observation points to the need for improved patient care in pre–end-stage renal failure. In the diabetic patient, dialysis should be started earlier than in the nondiabetic patient, and prophylactic vascular access should be established when the glomerular filtration rate is approximately 20 ml/min. Proposals to improve prognosis of the diabetic patient with renal failure include interdisciplinary care for the patients with renal disease, strict normotension, administration of ACE inhibitors, administration of lipid-lowering agents, near-normalization of anemia using recombinant human erythropoietin, and improvement of diabetic foot care in the patient on renal replacement therapy. Diabetes Care 22 (Suppl. 2):B80–B83, 1999 There is consensus that survival and rehabilitation of diabetic patients on renal replacement programs continue to be inferior to that of nondiabetic renal patients (1–3). This is all the more tragic because—at least in principle—diabetic nephropathy and end-stage renal failure from diabetic nephropathy are preventable conditions. Passa (4) stated recently "the diabetologists' dream is to reduce the nephrologists' work load until the latter are unemployed, at least as far as diabetic patients are concerned." Although it would certainly be desirable for this wish to become true, we expect that nephrologists will continue to stay in business for a long time. WHAT IS THE MAGNITUDE OF THE PROBLEM?— In the U.S. and Europe, renal disease in diabetic patients—not necessarily always Kimmelstiel Wilson's glomerulosclerosis—has become the single most important cause of end-stage renal failure, although great differences are found between countries (1,2). In the large registries, information concerning the relative proportion of patients with type 1 and type 2 diabetes is unreliable. Patients on insulin are listed as patients with type 1 diabetes—not a page of glory for nephrologists (6). In small registries (7,8) and local series (5), patients were categorized according to the National Diabetes Data Group's criteria, so these figures are more reliable. In southwest Germany and in northern Italy, there was a similar absolute number of type 1 diabetic patients admitted for renal replacement therapy, i.e., five patients per million per year in each area. In Germany, however, there was a dramatically higher admission rate for patients with type 2 diabetes, and type 2 diabetes accounted for >90% of all cases of diabetes. Presumably, the differences in incidence of renal failure in patients with type 2 diabetes largely explain the substantial differences of admission rates between countries. Is there a trend for incidence and prevalence to change with time? The proportion of diabetic patients among admissions for renal replacement therapy in Heidelberg University's program increased from 36 to 59% between 1990 and 1995 (9). This is certainly not a statistical artifact. Although there are countries in Europe, e.g., France and Spain, where the incidence of renal disease of diabetic patients is traditionally low, an increasing trend has been noted all over Europe (10), including these countries. For instance, the Catalan Registry (8) reported that acceptance for renal replacement therapy increased from 8 per million per year in 1984 to 26.6 per million per year in 1994. In France, the prevalence of diabetic patients in the dialysis population was 6% at the beginning of the decade (11). In 1995, it was already 15% in northern France. In 1996, Professor Hannedouche from Strassburg reported that no less than 40% of patients admitted for renal replacement therapy had diabetes. In this age of social insensitivity, the most convincing argument concerning the importance of a medical problem is to point to its financial consequences (9). The total German dialysis population is ~40,000; assuming that 40% of patients have diabetes (in good agreement with preliminary data of the German Registry) and estimating direct and indirect costs of dialysis treatment at 80,000 DM per year (possibly an underestimate), one arrives at a grand total of 1.3 billion DM per year that Germany spends for the treatment of diabetic patients by dialysis. Apart from these financial aspects, one must not forget the degree of human suffering that hides behind these figures and that is difficult to quantitate.
WHAT ARE THE CAUSES OF DEATH OF DIABETIC PATIENTS ON RENAL REPLACEMENT PROGRAMS?— If one wants to improve prognosis, clear data about survival and causes of deaths are required. As shown in Fig. 1, according to a recent prospective study, 5-year survival continues to be poor in type 1 and particularly in type 2 diabetic patients (12). Survival is as poor as in some gastrointestinal carcinomas. Figures have not much improved in the recent past (Table 1) (13). The major causes of death are cardiovascular, not only classical myocardial infarction, but also sudden death of unknown origin and other cardiac causes, particularly pumping failure. Among the noncardiac causes, septicemia (originating usually from a diabetic foot problem and not from the fistula) and progressive cachexia, with or without ultimate interruption of treatment, are common.
WHAT IS THE QUALITY OF MEDICAL CARE OF DIABETIC PATIENTS IN PRE–END-STAGE RENAL FAILURE?— If one tries to improve prognosis of a diabetic patient on renal replacement programs, it would be ludicrous to limit efforts to the patient in terminal uremia. Most problems accumulated before patients reached end-stage renal failure. This is illustrated by the fact that coronary stenosis is found in ~40% of patients admitted for renal replacement therapy. We are convinced that if one wishes to improve medical rehabilitation on dialysis or after transplantation, one has to improve medical care in the stage before renal failure has occurred. A few observations will suffice to document that there is considerable room for improvement in this respect. In 1991, we looked at control of blood pressure, hyperlipidemia, retinopathy, and several other items in 169 diabetic patients who were admitted for renal replacement therapy to 18 German dialysis centers (14). Despite antihypertensive treatment, only 20% were normotensive, only 5% received lipid-lowering drugs, and less than half had seen an ophthalmologist in the year preceding admission to renal replacement therapy.
The St. Vincent declaration postulated that care of the diabetic patient should be improved. One would therefore anticipate (15) that today's quality of medical treatment is better and that patients are admitted to nephrologists at an earlier stage of renal dysfunction. Table 2 gives some details concerning renal function and medical management of nine consecutive diabetic patients, all type 2, admitted in the first 6 months of 1997 to the renal unit of the University of Heidelberg. The findings are those observed at the time of admission. Median endogenous creatinine clearance was 10 ml/min, and the highest value was no more than 20 ml/min—advanced renal failure in all, with no chance of success for measures to retard progression. Serum creatinine was surprisingly low, however. This is an important message for the nonnephrologist: in these often malnourished, cachectic patients with low body mass and lowish serum creatinine, an advanced stage of renal failure (as indicated by creatinine clearance) may be present despite low serum creatinine. The risk of misinterpretation is particularly great because serum urea is also lowish as a result of uremic anorexia with low food and protein intake. Vascular access had been established in none of the patients, necessitating emergency access via jugular catheter, thus increasing risk, decreasing dialysis efficacy, and prolonging hospital stay.
In 1991, median systolic blood pressure on admission was 220 mmHg (14). Although in 1991 it was abysmal, in 1997 it was only catastrophic, with median systolic blood pressure now being 180 mmHg (range 140–230 mmHg). Poor control of hypertension is not fully explained by undertreatment, because an average of 2.8 classes of antihypertensive agents had been used by the referring physicians. This point is also illustrated by the difficulty of achieving normotension in our own outpatient clinic (Fig. 2), despite the facts that a median of four different antihypertensive classes was used, that patients were instructed to perform blood pressure self-measurement, and that ambulatory blood pressure was measured frequently. In Table 2, the median HbA1c concentration appears acceptable. But one should consider that these patients were anorectic, had reduced food intake, and had decreased body weight. The observation of high LDL cholesterol is particularly important: in prospective trials, cholesterol concentration was predictive of cardiac death in the dialyzed diabetic (Table 3) (13,16), whereas in the dialyzed nondiabetic patients, the predictive effect of cholesterol is masked by the confounding action of malnutrition (17). It is also of note that even at the time when renal replacement therapy is started, a large proportion of patients has already coronarographic evidence of coronary artery disease (18).
Such disappointing observations are not unique to our unit. Pommer et al. (19) in Berlin noted that 77% of diabetic patients were referred at a stage when glomerular filtration rate was <30 ml/min. Only 2.5% were normotensive according to Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure criteria, and only a minority had received ACE inhibitors. It is quite obvious, therefore, that preterminal care of the diabetic patient has to be improved substantially (4). This will require adequate information and education of physicians, notably general practitioners, who have no expertise in nephrology or diabetology, and also instruction of the patients, who must be more closely involved in their own treatment. HOW CAN PROGNOSIS BE IMPROVED IN DIABETIC PATIENTS ON RENAL REPLACEMENT THERAPY?— Based on a priori consideration, it is sensible to assume that the following measures that we propose will improve survival and medical rehabilitation of the diabetic patient on renal replacement therapy:
References 2. Raine AE: Epidemiology, development and treatment of endstage renal failure in type 2 (non-insulin-dependent) diabetic patients in Europe. Diabetologia 36:99–104, 1993 3. Gusmann RA, Stead WW, Robinson RR: Physical activity and employment status of patients on maintenance hemodialysis. N Engl J Med 304:309–313, 1981 4. Passa P: Diabetic nephropathy in the NIDDM patient on the interface between diabetology and nephrology: what do we have to improve? Nephrol Dial Transplant 12:1316–1318, 1997 5. Lippert J, Ritz E, Schwarzbeck A, Schneider P: The rising tide of endstage renal faiulre from diabetic nephropathy type II: an epidemiological analysis. Nephrol Dial Transplant 10:462–467, 1995 6. Ritz E, Stefanski A: Diabetic nephropathy in type II diabetes. Am J Kidney Dis 27:167–194, 1996 7. Marcelli D, Spotti D, Conte F, Limido A, Lonati F, Malberti F, Locatelli F: Prognosis of diabetic patients on dialysis: analysis of Lombardy Registry data. Nephrol Dial Transplant 10:1895–1901, 1995 8. Rodriguez JA, Cleries M, Vela E, and the Renal Registry Committee: Diabetic patients on renal replacement therapy: analysis of Catalan registry data. Nephrol Dial Transplant 12:2501–2509, 1997 9. Ritz E, Lippert J, Keller C: Rapider Anstieg der Zahl niereninsuffizienter Typ II Diabetiker (Editorial). Dtsch Med Wschr 121:1247, 1996 10. Raine AEG: Evolution worldwide of the treatment of patients with advanced diabetic nephropathy by renal replacement therapy. In The Kidney and Hypertension in Diabetes Mellitus. 3rd ed. Mogensen CE, Ed. Boston, Kluwer Academic, 1996, p. 473–481 11. Zmirou D, Benhamou PY, Cordonnier D, Borgel F, Balducci F, Papoz L, Halmimi S: Diabetes mellitus prevalence among dialysed patients in France (UREMIDIAB study). Nephrol Dial Transplant 7:1092–1097, 1992 12. Koch M, Kutkuhn B, Grabensee B, Ritz E: Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients: a prospective study in 412 subjects. Nephrol Dial Transplant. 12:2603–2611, 1997 13. Koch M, Thomas B, Tschöpe W, Ritz E: Survival and predictors of death in dialysed diabetic patients. Diabetologia 36:1113–1117, 1993 14. Koch M, Tschöpe W, Ritz E: Ist die Betreuung niereninsuffizienter Diabetiker in der prädialytischen Phase verbesserungsbedürftig? Dtsch Med Wschr 116:1543–1548, 1991 15. Ritz E, Strzelczyk P: Prävention der terminalen Niereninsuffizienz bei Diabetes mellitus—Stand in Deutschland 1996. In Die Forderungen von St. Vincent: Stand 1996 in Deutschland. Berger M, Trautner C, Eds. Mainz, Germany, Kirchheim Verlag, p. 55–64, 1996 16. Tschöpe W, Koch M, Thomas B, Ritz E: Serum lipids predict cardiac death in diabetic patients on maintenance hemodialysis: results of a prospective study: the German Study Group Diabetes and Uremia. Nephron 64:354–358, 1993 17. Ritz E: Why are lipids not predictive of cardiovascular death in the dialysis patient? Miner Electrolyte Metab 22:9–12, 1996 18. Manske CL, Wang Y, Rector T, Wilson RF, White CW: Coronary revascularisation in insulin-dependent diabetic patients with chronic renal failure. Lancet 340:998–1002, 1992 19. Pommer W, Bressel F, Chen F, Molzahn M: There is room for improvement of preterminal care in diabetic patients with endstage renal failure: the epidemiological evidence in Germany. Nephrol Dial Transplant 12:1318–1321, 1997 20. Port FK, Wolfe RA, Mauger EA, Berling DP, Jiang K: Comparison of survival probabilities for dialysis patients vs. cadaveric renal transplant recipients. JAMA 270:1339–1343, 1993 21. Manske CL, Thomas W, Wang Y, Wilson RF: Screening diabetic transplant candidates for coronary artery disease: identification of a low risk subgroup. Kidney Int 44:617–621, 1993 22. Koch M, Gradaus F, Schoebel FC, Leschke M, Grabensee B: Relevance of conventional cardiovascular risk factors for the prediction of coronary artery disease in diabetic patients on renal replacement therapy. Nephrol Dial Transplant 12:1187–1191, 1997 23. Ritz E, Koch M: Morbidity and mortality due to hypertension in patients with renal failure. Am J Kidney Dis 21:113–118, 1993 24. Charra B, Calemard E, Ruffet M, Chazot C, Terrat JC, Vanel T, Leurent G: Survival as an index of adequacy of dialysis. Kidney Int 41:1286–1291, 1992 25. Silberberg JS, Racine N, Barre P, Sniderman AD: Regression of left ventricular hypertrophy in dialysis patients following correction of anemia with recombinant human erythropoietin. Can J Cardiol 6:1–4, 1990 26. Cannella G, Paoletti E, Delfino R, Peloso G, Molinari S, Traverso GB: Regression of left ventricular hypertrophy in hypertensive dialyzed uremic patients on longterm antihypertensive therapy. Kidney Int 44:881–886, 1993 27. Ritz E, Amann K: Optimal hemoglobin during treatment with recombinant human erythropoietin. Nephrol Dial Transplant 13(Suppl. 2):16–22, 1998 From the Department of Internal Medicine (E.R., D.F., V.S.), Ruperto-Carola University, Heidelberg; and the Clinic for Nephrology and Rheumatology (M.K.), Düsseldorf, Germany. Address correspondence and reprint requests to Eberhard Ritz, MD, Department Internal Medicine, University of Heidelberg, Bergheimer Strasse 56 a, 69115 Heidelberg, Germany. Received for publication 27 May 1998 and accepted in revised form 20 August 1998. This article is based on a presentation at a satellite symposium of the 16th International Diabetes Federation Congress. The symposium and the publication of this article were made possible by educational grants from Hoechst Marion Roussel AG. Copyright © 1999 American Diabetes Association For Technical Issues contact webmaster@diabetes.org |
, n =
69) and diabetic (
, n = 26) patients with impaired renal function followed in
the outpatient clinic in the Renal Unit Heidelberg. Box and whiskers-plot presentation of
data. Note frequent failure to achieve target blood pressure, although, on average, four
classes (range 1–7) of antihypertensive agents were given.