NEFROLOGÍA. Vol. XXII. Número 4. 2002 EDITORIALES Halting the progression of renal disease: where we stand? R. C. Campbell, M.D. 1, 3 and G. Remuzzi, M.D. 1, 2 1 «Mario Negri» Institute for Pharmacological Research, Negri Bergamo Laboratories, Bergamo ­ Italy. 2Unit of Nephrology and Dialysis, Ospedali Riuniti di Bergamo, Bergamo ­ Italy. 3Division of Nephrology, Department of Medicine, University of Alabama, Birmingham, EE.UU. End stage renal disease (ESRD) is increasing at an alarming rate worldwide. During the last decade in the United States, the number of patients reaching ESRD jumped to 372,000 1. Europe and Japan are expected to have a similar trend. The increase in ESRD is largely fueled by a rise in the incidence of type 2 diabetes and an aging population 2. The epidemic of type 2 diabetes, however, is not limited to the United States, Europe and Japan. The number of adults with diabetes worldwide is expected to reach 300 million by the year 2025, with 75% of those affected in non-industrialized nations 3. As approximately 27% of type 2 diabetics are at risk for developing nephropathy after 20 years of diabetes 4, these statistics present a staggering challenge to health care providers and patients alike. From a purely financial standpoint, ESRD care is tremendously expensive, and the cost of the U.S. dialysis program is expected to double to $28 billion US by 2010 5. This is mirrored in Europe, where dialysis care consumes a disproportionate percentage of health care budgets 6. The cost of providing dialysis may be prohibitive for many developing countries and for patients in these areas, ESRD means death from uremia. Even if dialysis is available, the view from the patient's perspective is grim; besides the severe life style modifications required by dialysis, those afflicted with ESRD face significant morbidity and mortality. Dialysis patients have a much short life expectancy of aged matched controls, with cardiovascular disease being the largest single cause of death 5. Patients starting dialysis are also older and sicker; the average age of a patient on dialysis in the United States had risen to 62 years from 58 years during the last decade, and Correspondencia: Ruth Campbell, M.D. «Mario Negri» Institute for Pharmacological Research Negri Bergamo Laboratories Via Gavaazzeni, 11 24125 Bergamo, Italy more than 30% have a history of ischemic heart disease 7. The increase in morbidity and mortality from renal disease is not limited to those with ESRD; chronic renal insufficiency (CRI) itself is also a risk factor for cardiovascular disease, and patients with microalbuminuria, increased serum creatinine or decreased creatinine clearance are at greater risk for cardiovascular disease than those without 8. Clearly, the best solution to the problems of CRI and ESRD is to find effective therapies to slow the progression of established nephropathy, and in diseases where nephropathy is likely to develop, to find strategies to prevent its emergence. There are effective treatment options available today for patients with both diabetic and non diabetic chronic nephropathy. Hypertension and proteinuria have emerged as major factors that predict the risk of progression to ESRD and treatment of these disorders is renoprotective. Hypertension, also an independent cardiovascular risk factor, was found in the MDRD study to predict the risk of progression of CRI in non-diabetic chronic renal insufficiency 9. Both type 1 and type 2 diabetics with elevated blood pressure are at higher risk for progression, and treatment of elevated blood pressure reduces this risk 10. Proteinuria, once thought to be merely a marker of renal disease, has been also established as a major risk factor in identifying patients at risk for progressing to ESRD 9. Excessive filtered proteins causes inflammation and scarring in the proximal tubules and interstitium, which ultimately may lead to ESRD 11 and agents that decrease proteinuria are renal protective 12. Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin 2 receptor antagonists (ARA) have been shown in a number of studies for both diabetic and non diabetic patients to reduce proteinuria in a mechanism that is not directly linked to reduction of systemic blood pressure 11. The REIN trial, which investigated the effect of ACE-I vs conventional blood 303 R. C. CAMPBELL and G. REMUZZI pressure control, found that treatment with ACE-I reduced proteinuria, and resulted in a sustained slowing of the loss of GFR 13. This study also included patients with severely impaired renal insufficiency, and found that these patients benefited from ACE-I with an acceptable side-effect profile 14. ACE-I have similar benefits in type I diabetic nephropathy and slow progression to ESRD 15. The recently published RENAAL 16 and IDNT 17 trials also demonstrated a beneficial effect of treatment with ARA in the treatment of overt type 2 diabetic nephropathy. These trials included patients with a maximum serum creatinine of 3.0 mg/dL and had a relatively low rate of side effects such as hyperkalemia. ARA also successfully slowed the development of diabetic nephropathy in type 2 18 and ACE-I in type 1 19 diabetic patients with microalbuminuria. These drugs are also cost effective, and are associated with significant cost savings 20, 21. In addition to reducing proteinuria, agents that block the RAS also have significant cardioprotective benefits. ACE-I and ARA are effective in treating congestive heart failure, and in the HOPE trial, treatment with ACE-I was shown to effectively reduce the risk of death from cardiovascular causes in patients at risk for cardiac disease 22. The non-diabetic patient group that received the ACE-I in the HOPE trial also developed less diabetes than the control group, for reasons that are not fully understood 23. Unfortunately, not all patients respond to these measures. In the IDNT 17 and RENAAL 16 trial, 14.2% and 19.6% respectively, of patients in the ARA group still progressed to ESRD. The REIN trial found that women responded better to ACE-I than men, and that ACE genotype was important in predicting a male patient's response 24. Preliminary data suggest that an aggressive, multi-system approach of blood pressure control, blockade of the RAS, treatment of dyslipidemia and smoking cessation 11, 25 may be renal protective in these patients. Newer therapies are being developed to address the needs of those who do not respond to ACE-I or ARA and include endothelin antagonists and vasopeptidase inhibitors 11. Despite these advances, many patients are not aggressively treated for hypertension, proteinuria and renal insufficiency. In the general U.S. population, control of elevated blood pressure is very poor and less than 25% of hypertensive patients have their blood pressure at target levels of < 140/90 26. These data include all patients; little is known about the adequacy of control in those with renal insufficiency. A recent study of 1,247 type 2 diabetics with hypertension had similar findings; only 26.7% met the target goal of 130/85 27. Some physicians seem unaware of the risk/benefit ratio of treatment with 304 ACE-I or ARA. There are misconceptions regarding the safety of ACE-I use in patients with renal insufficiency, with some authors suggesting that they not be used in patients with creatinine levels greater than 3 mg/dL 28. Acute renal failure due to bilateral renal artery stenosis and hyperkalemia are often feared 29, despite the safety profiles of the clinical trials using ACE-I and ARA in patients with renal disease 13, 16, 17. One recent study found that in patients with congestive heart failure, ACE-I were less likely to be prescribed when the serum creatinine was greater than 3 mg/dL 31. Interestingly, this study found that the patients who benefited the most from ACEI use were those with a serum creatinine > 3 mg/dL. While it would be easy to blame this approach on non-nephrologists, evidence suggests that 32 nephrologists are just as likely not to prescribe an ACE-I for patients with renal insufficiency as primary care physicians. Improved physician education is strongly needed to ensure that patients with renal insufficiency benefit from the available proven treatment strategies to reduce the risk of ESRD. A concerted, sustained effort to prevent progression to ESRD is needed if we are to reduce the burden of dialysis. Physicians must be aware that there are powerful tools to reduce, and perhaps halt, progression to ESRD and we should not hesitate to use them. BIBLIOGRAFÍA 1. Collins A, Xue J, Ma J, Louis T: Estimating the number of patients and medicare costs for end stage renal disease in the US to the year 2010. Journal of the American Society of Nephrology 11: 113A, 2000. 2. Excerpts From the United States Renal Data System 2001 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. American Journal of Kidney Diseases 38: 53-68, 2001. 3. Fall C: Non-industrialised countries and affluence. British Medical Bulletin 60: 33-50, 2001. 4. Hasslacher C, Ritz E, Wahl P, Michael C: Similar risks of nephropathy in patients with type I or type II diabetes mellitus. Nephrology Dialysis and Transplant 4: 859-863, 1989. 5. US Renal Data System: USRDS 2000 Annual Data Report, in, Bethesda, MD, The National Institues of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2000. 6. De Vecchi A, Dratwa M, Wiedemann M: Healthcare systems and end-stage renal disease (ESRD) therapies--an international review: costs and reimbursement/funding of ESRD therapies. Nephrology Dialysis and Transplant 14: 31-41, 1999. 7. Anonymous: The USRDS and its products. United States Renal Data System. American Journal of Kidney Diseases 32 s: S20-194, 1998. 8. Ruilope L, Veldhuisen Dv, Ritz R, Luscher T: Renal function: the Cinderella of cardiovascular risk profile. Journal of the American College of Cardiology 38: 1782-1787, 2001. 9. Peterson J, Adler S, Burkart J: Blood pressure control, proteinuria, and the progression of renal disease. Annals of Internal Medicine 123: 754-762, 1995. HALTING THE PROGRESSION OF RENAL DISEASE 10. Bakris G, Williams M, Dworkin L, Elliott W, M ME, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J: Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation, Hypertension and Diabetes Executive Committees Working Group. American Journal of Kidney Diseases 36: 646-661, 2000. 11. Ruggenenti P, Schieppati A, Remuzzi G: Progression, remission, regression of chronic renal disease. Lancet 357: 1601-1608, 2001. 12. Remuzzi G, Bertani T: Pathophysiology of Progressive Nephropathies. New England Journal of Medicine 339: 1448-1456, 1998. 13. GISEN: Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 349: 1857-1863, 1997. 14. Ruggenenti P, Perna A, Remuzzi G: ACE inhibitors to prevent end-stage renal disease: when to start and why possibly never to stop: a post hoc analysis of the REIN trial results. Ramipril Efficacy in Nephropathy. Journal of the American Society of Nephrology 12: 2832-2837, 2001. 15. Lewis E, Hunsicker L, Bain R, Rohde R: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. New England Journal of Medicine 239: 1456-1462, 1993. 16. Brenner B, Cooper M, Zeeuw Dd, Keane W, Mitch W, Parving H, Remuzzi G, Snapinn S, Zhang Z, Shahinfar S: Effects of losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy. New England Journal of Medicine 345: 861-869, 2001. 17. Lewis E, Hunsicker L, Clarke W, Berl T, Pohl M, Lewis J, Ritz E, Atkins R, Rohde R, Raz I: Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes. New England Journal of Medicine 345: 851-860, 2001. 18. Parving H, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P: The Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes. New England Journal of Medicine 354: 870-878, 2001. 19. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enyzme inhibitors? Annals of Internal Medicine 134: 370-379, 2001. 20. Ruggenenti P, Pagano E, Tammuzzo L, Benini R, Garattini L, Remuzzi G: Ramipril prolongs life and is cost effective in chronic proteinuric nephropathies. Kidney International 59: 286-294, 2001. 21. Hogan T, Elliott W, Seto A, Bakris G: Antihypertensive Treatment with and without Benazepril in Patients with Chronic Renal Insufficiency: a US Economic Evaluation for patients with renal insufficiency. Pharmacoeconomics 20: 37-47, 2002. 22. Effects of ramipril on cardiovascular and micorvascular outcomes in people with diabetes mellitus: results of the HOP study and MICRO-HOPE substudy. Lancet 355: 253-259, 2000. 23. Yusuf S, Gerstein H, Hoogwerf B, Pogue J, Bosch J, Wolffenbuttel B, Zinman B: Ramipril and the development of diabetes. Journal of the American Medical Association 286: 1882-1885, 2001. 24. Perna A, Ruggenenti P, Testa A, Spoto B, Benini R, Misefari V, Remuzzi G, Zoccali C: ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies. Kidney International 57: 274-281, 2000. 25. Hovind P, Rossing P, Tarnow L, Toft H, Parving J, Parving H: Remission of nephrotic-range albuminuria in type 1 diabetic patients. Diabetes Care 24: 1972-1977, 2001. 26. Sixth report from the Joint Committee on the Detection, Evaluation and Treatment of High Blood Pressure. Archives of Internal Medicine 157: 2413, 1997. 27. McFarlane S, Jacober S, Winer N, Kaur J, Castro J, Wui M, Gliwa A, Gizycki HV, Sowers J: Control of cardiovascular risk factors in patients with diabetes and hypertension at urban academic medical centers. Diabetes Care 25: 718723, 2002. 28. Moser M: Angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists and calcium channel blocking agents: a review of potential benefits and possible adverse reactions. Journal of the American College of Cardiology 29: 1414-1421, 1997. 29. Ruggenenti P, Remuzzi G: Angiotensin converting enzyme inhibition in patients with impaired renal function: helpful or harmful, in Sixth European Meetin on Hypertension, edited by Unger T, Palu CD, Milan, Italy, Media Medica Publications, Ltd, 1993, pp. 27-40. 30. GISEN: Randomized placebo-controlled trial effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 349: 1857-1863, 1997. 31. Frances C, Noguchi H, Massie B, Browner W, McClellan M: Are We Inhibited? Renal Insufficiency Should Not Preclude the Use of ACE Inhibitors for Patients With Myocardial Infarction and Depressed Left Ventricular Function. Archives of Internal Medicine 160: 2645-2650, 2000. 32. Nissenson A, Collins A, Hurley J, Petersen H, Pereira B, Steinberg E: Opportunities for Improving the Care of Patient with Chronic Renal Insufficiency: Current Practice Patterns. Journal of the American Society of Nephrology 12: 1713-1720, 2001. 305