DISCUSSION BOARD
      PANEL DE DISCUSION

        CARDIOVASCULAR DISEASE IN CHRONIC RENAL DISEASE

        Mai Ots, M.D.,Sc.D.(med)
        Division of Nephrology, Department of Internal Medicine
        University of Tartu
        6 Puusepa Str. Tartu, 51014, ESTONIA

        Tel: 372-7-448-272. Fax: 372-7-448-607 E-mail: mai.ots@kliinikum.ee

        Key words: atherosclerosis, glomerulosclerosis, hypertension, renal failure


        INTRODUCTION

        Cardiovascular disease (CVD) is the leading cause of mortality among patients with progressive renal failure and renal replacement therapy. The risk of atherosclerotic CVD in patients with chronic renal failure, especially patients on renal replacement therapy, has shown to be 10-20 times greater than in the general population. Therefore, patients with chronic renal disease should be considered in the highest risk group for subsequent cardiovascular events and proper preventive measures should be undertaken. The care of chronic renal failure patients cannot start in the period of end-stage renal disease (ESRD) or after the initiation of dialysis but must set into motion when progressive renal disease is diagnosed and renal failure first begins. Optimal treatment prevents detrimental influence of uraemia on the metabolic balance, function, and structure of the body. The National Kidney Foundation Task Force recommendations stress the importance of preventive measures of renal patients early in the course of kidney failure when these can be most effective, cost efficient, and of greatest benefit to patients and to society. Reduction of both the "traditional" atherosclerosis risk factors as well as specific risk factors related to chronic renal failure should be one of the main targets of early management of patients with chronic renal disease (1,2,3).


        RISK FACTORS OF ATHEROSCLEROSIS IN CHRONIC RENAL DISEASE

        Several risk factors for CVD manifestations in chronic renal disease patients are similar to the progression of atherosclerosis in general population because of the higher incidence of ESRD in elderly. Atherosclerosis is a multifactorial disease. The approach to the "traditional" CVD risk factors like hypertension, diabetes, obesity, hyperlipidemia, oxidative stress, smoking, physical inactivity should be guided by the principle that chronic renal disease patients belong into the highest risk group for subsequent CVD complications. During the course of the renal disease progression excess risk may appear that influence significantly the outcome (4). Excellent reviews about the importance of various risk factors were recently published in the American Journal of Kidney Diseases (Supplement N 5, 1998).

        Hypertension and diabetes are serious risk factors for the development of atherosclerosis, and for all-cause mortality (5,6). Hypertension is also a significant risk factor for the development of glomerulosclerosis in various etiologies (7,8). Thus, kidney disease may be either a cause or consequence of hypertension and atherosclerotic cardiovascular disease. In the general population and among patients with chronic renal disease, CVD is more prevalent among individuals with diabetes than those without diabetes. According to the data of three large registries covering the United States, Europe, and Australia and New Zealand it appears that diabetic nephropathy is the main cause of end-stage renal disease in many countries. And, hypertension and diseases of the large arteries constitute the second major cause of renal failure (9). Hypertension complicates the clinical course of patients with chronic renal failure and, if inadequately controlled, may hasten the deterioration of renal function (10,11). On the other hand, the presence of hypertension in chronic renal disease is associated with adverse outcomes of cardiovascular disease. The development of hypertension among chronic renal disease patients involves various pathogenic factors: 1) sodium and volume balance, 2) renin-angiotensin aldosterone stimulation, 3) increased sympathetic activity, 4) endogenous digitalis-like factors, 5) endothelium-derived factors, 6) erythropoetin administration, 7) nephron number, 8) hyperparathyroidism and calcified arterial tree, 9) renal vascular disease, 10) worsening of pre-existing essential hypertension (12).

        Patients with chronic renal disease should be screened also for hyperlipidemia because the prevalence of hyperlipidemia is increased in patients with chronic renal insufficiency compared with general population. Atherogenic lipoproteins are major risk factors implicated in the pathogenesis of atherosclerotic cardiovascular disease. It has been suggested that determination of at least triglycerides, total, HDL and LDL cholesterol levels should be regularly monitored in predialysis patients and renal replacement therapy patients (13). Other cardiovascular risk factors also play an important role in the progression of atherosclerotic CVD. However, smoking, obesity or physical inactivity has not been intensively investigated in the early stages of renal disease (4,14-17).

        Several specific risk factors due to chronic renal failure significantly influence the progression of atherosclerosis. The excess risk, which contribute to the progression of atherosclerosis may be caused by the hemodynamic and metabolic factors like progressive proteinuria, hypoalbuminemia, malnutrition, electrolyte imbalance, increased extracellular volume, anaemia, uremic toxins, hyperphosphatemia, hyperuricemia, high levels of fibrinogen and homocysteine (18-23). Anaemia is associated with the progression of left ventricular hypertrophy in chronic renal failure patients and should be treated with iron and erythropoetin in order to achieve the target hematocrit. A tendency toward phosphate retention begins early in renal disease and diet modification as well as drug treatment of secondary hyperparathyroidism is often necessary before the initiation of dialysis (24,25).

        Recently, it has been shown that hyperhomocyst(e)inemia is an independent risk factor for CVD in the general population and in patients with chronic renal disease. A combination of high-dose folic acid, vitamin B12 and vitamin B6 reduces homocysteine levels by 25%, which may restore normal levels in patients with chronic renal insufficiency. However, the effects of decreasing homocysteine levels on the risk for CVD are not exactly known (1,20).



        PROGRESSION OF ATHEROSCLEROSIS AND GLOMERULOSCLEROSIS

        As described, various risk factors and mechanisms are involved in the progression of premature atherosclerosis in renal failure patients. Risk factors such as hypertension, humoral factors, hyperlipidemia, lipid deposition in vessels and later development of atherosclerotic lesions play a central role in the progression. Cardiovascular risk factors play important role also in the progressive renal disease (26). Moreover, in-vitro and in-vivo studies have shown that atherosclerosis and glomerulosclerosis are pathobiologically analogous processes where several common biochemical and histological abnormalities are noticed (27,28). There is strong evidence that atherosclerosis should be fundamentally viewed as chronic inflammatory disease as for instance glomerulosclerosis, cirrhosis, rheumatoidarthritis and pulmonary fibrosis (26). Hormonal, cellular and molecular responses of each particular tissue or organ depends on its characteristic architecture. Similar characteristic lesions for atherosclerosis and glomerulosclerosis are endothelial-cell injury and dysfunction. Hyperlipidemia and atherogenic lipoproteins can be the initiating factors for both conditions because abnormalities in lipids and lipoproteins are often present. Usually hyperlipidemia is more associated with ongoing atherosclerotic process (29). Nevertheless, experimental studies have shown that lipid abnormalities themselves can influence the progression of renal disease and lipid oxidation has been increased in animal and human glomerular diseases (30,31). Increased nephron oxygen radical generation leads to renal tissue lipid peroxidation. Antilipemic therapy (32) may be beneficial in ameliorating renal disease progression.

        Central to the pathogenesis of atherosclerosis is the interaction of blood cells and endothelial cells with subsequent macrophage accumulation, proliferation of smooth muscle cells and enhanced production of collagen (26). The mechanisms that appear to be responsible for this increased proliferative response are growth factors, cytokines, and local alterations in the extracellular matrix proteins (ECM). Participation of cellular and molecular factors and subsequent accumulation of ECM proteins are closely related also with the kidney disease progression (33). Similar to atherosclerosis, the kidney fibrosis in human or experimental glomerulonephritides and even in classical glomerulosclerotic model e.g. remnant kidney involves inflammatory component. Infiltration of mononuclear leukocytes in glomerular and tubulointerstitial areas, upregulation of proinflammatory cytokines and growth factors after the initiation of the disease play important role in the progression (34-37). The glomerulosclerosis process includes mesangial expansion with mesangial cell proliferation, mesangial foam cell accumulation, tissue necrosis, and eventual sclerosis. Substances that interfere with the interaction between the different cell types, such as endothelial cells, macrophages, and platelets, and with the proliferative responses of both vascular and mesangial cells may be of therapeutic value in both diseases (26,38).

        Much attention has recently been paid to chemokines and also, for growth factors, e.g. transforming growth factor-β (TGF-β) because the key actions of this growth factor is the induction of the ECM production. Specific matrix proteins are known to be induced by TGF-β, which were increased in experimental kidney diseases rat glomeruli. TGF-β, monocyte chemoattractant protein -1 (MCP-1) mRNA and protein expression as well as macrophage infiltration dynamics have been investigated in experimental diabetic nephropathy (39). In these studies sustained TGF-β and MCP-1 overexpression was also observed. This particular gene expression was closely associated with the extent of macrophage infiltration and proteinuria (39). The principal factors associated with macrophage accumulation in the lesions of atherosclerosis include also macrophage colony stimulating factor and MCP-1 (26).

        RECOMMENDATIONS

        Strategies for risk factor identification and reduction should target both the traditional coronary risk factors and specific risk factors related to chronic renal disease. Hypertension is a major risk factor for all types of atherosclerotic CVD. The prevalence of hypertension in chronic renal disease patients ranges 60-100% and most patients require antihypertensive treatment. Renin-angiotensin system inhibitors proved its effectiveness in the treatment of essential hypertension and congestive heart failure (40,41). Studies on experimental and human diabetic and nondiabetic renal diseases revealed that the progression of the renal disease can be slowed by renin-angiotensin system blockade that modulate hemodynamic and non-hemodynamic factors contributing to the progression of glomerulosclerosis (42-44). Thus, renin-angiotensin system blocking agents have been proved to be vaso- and renoprotective and, therefore, prescribed not only for antihypertensive but also for vaso- and renoprotective purposes in diabetic nephropathy and in other chronic glomerular diseases with and/or without systemic hypertension.

        Monitoring and accurate treatment of patients with chronic renal disease needs specialised training. It is reasonable to follow current clinical guidelines, which are based on the highest level of current evidence (24,45). Various national organisations have developed clinical guidelines regarding prevention of CVD in the general population. These are the interventions the Task Force considered in chronic renal disease (1). In addition, several specific risk reduction strategies were included. The report of the National Kidney Foundation Task Force on CVD in chronic renal failure is a first attempt to provide evidence-based recommendations for this holistic approach to the care of patients with renal disease (2).

        REFERENCES

          1. Levey AS, Beto JA, Coronado BE, et.al: Controlling the Epidemic of Cardiovascular Disease in Chronic Renal Disease: What Do We know? What Do We Need To Learn? Where Do We Go From Here? Am J Kidney Dis 1998;32,5:853-906

          2. Eknoyan G: On the epidemic of cardiovascular disease in patients with chronic renal failure: A first step to improve the outcomes. Am J Kidney Dis 1998;32,5(S3):S1-S4

          3. Ismail N, Neyra R, Hakim R: The medical and economical advantages of early referral of chronic renal failure patients to renal specialists. Nephrol Dial Transpl 1998; 13:246-250

          4. Foley RN, Parfrey PS, Sarnak MJ: Clinical Epidemiology of Cardiovascular Disease in Chronic Renal Disease. Am J Kidney Dis 1998;32,5,Suppl5:S112-S119

          5. Ross R: The pathogenesis of atherosclerosis - an update. N Engl J Med 1986; 314:488-500.

          6. O'Donnell CJ, Ridker PM, Glynn RJ, and et.al: Hypertension and borderline isolated systolic hypertension increase risks of cardiovascular disease and mortality in male physicians. Circulation 1997;95:1132-1137.

          7. Oldrizzi L, Rugiu C, De Biase V, and et.al: The Place of Hypertension Among the Risk Factors for Renal Function in Chronic Renal Failure. Am J Kidney Dis 1993;21:119-123.

          8. Klag MJ, Whelton PK, Randall BL, and et.al: Blood pressure and end-stage renal disease in men. N Engl J Med 1996;334:13-18.

          9. Maisonneuve, P, Agodoa L, Gellert R, and et.al: Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: Results from an international comparative study. Am J Kidney Dis 2000;35;1:157-165

          10. Johnston CI, Millar JA, McGrath BP, Matthews PG: Long-term effects of captopril (SQ14 225) on blood pressure and hormone levels in essential hypertension. Lancet 1979; 2:493-6.

          11. Turini GA, Brunner HR, Gribic M, Waeber B, Gavras H: Improvement of chronic congestive heart failure by oral captopril. Lancet 1979; 1213-1215.

          12. Mailloux LU, Haley WE: Hypertension in the ESRD patient: pathophysiology, therapy, outcomes, and future directions. Am J Kidney Dis 1998; 32,5:705-719

          13. Kasiske BL: Hyperlipidemia in Patients With Chronic Renal Disease. Am J Kidney Dis 1998;32,5,Suppl5:S142-156

          14. Orth SR, Ritz E, Schrier RW: The renal risks of smoking. Kidney Int 1997; 51:1669-1677.

          15. Schmieder RE, Rockstroh JK: Obesity and hypertension. Curr Opin Nephrol Hypertens 1994; 3:546-549

          16. Ma KW, Greene EL, Raij L: Cardiovascular risk factors in chronic renal failure and hemodialysis populations. Am J Kidney Dis 1992; 19:505-513.78.

          17. Beto JA, Bansal VK: Interventions for Other Risk Factors: Tobacco Use, Physical Inactivity, Menopause, and Homocysteine. Am J Kidney Dis 1998;32,5,Suppl5:S172-S184

          18. Bergström J, Lindholm B: Malnutrition, Cardiac Disease, and Mortality: An Integrated Point of View. Am J Kidney Dis 1998; 32,5:834-841

          19. Stenvinkel P, Heimbrüger O, Paultre F, et.al: Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999; 55:1899-1911

          20. Block GA, Hulbert-Shearon TE, Levin NW et al. Association of serum phosphorus and calcium phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis. 1998; 31:607-617

          21. Manns BJ, Burgess ED, Hyndman ME, et.al: Hyperhomocyst(e)inemia and the Prevalence of Atherosclerotic Vascular Disease in Patients With End-Stage Renal Disease. Am J Kidney Dis 1998; 32,5:669-677

          22. Bostom AG, Shemin D, Verhoef P, et.al: Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients. Arterioscler Thromb Vasc Biol 1997;17:2554-2558

          23. Puig JG, Ruilope LM: Uric Acid as a cardiovascular risk factor in arterial hypertension. J Hypertens 1999;17(7):869-872

          24. Optimizing Anaemia Therapy in Chronic Renal Failure. Nephrol Dial Transplantation 1999;14:Suppl2

          25. Fournier A, Moriniere P, Ben Hamida F, et.al: Use of alkaline calcium salts as phosphate binder in uremic patients. Kidney Int Suppl 1992;38:S50

          26. Delmez JA, Slatopolsky E: Hyperphosphatemia:Its Consequences and treatment in Chronic renal failure. Am J Kidney Dis 1992;19:303

          27. Ross R: Atherosclerosis – An Inflammatory Disease. New Engl J Med 1999;340,2:115-126

          28. Keane WF, Kasiske BL, O'Donnell MP: Lipids and progressive glomerulosclerosis. A model analogous to atherosclerosis. Am J Nephrol 1988; 8:261-271.

          29. Diamond JR: Analogous pathobiologic mechanisms in glomerulosclerosis and atherosclerosis. Kidney Int Suppl 1991; S29-34

          30. London GM, Drueke TB: Atherosclerosis and arteriosclerosis in chronic renal failure. Kidney Int 1997; 51:1678-1695.

          31. Schrier RW, Shapiro JI, Chan L, Harris DCH: Increased Nephron Oxygen Consumption: Potential Role in Progression of Chronic Renal Failure. Am J Kidney Dis 1994; 23:176-182.

          32. Turi S, Nemeth I, Torkos A, Saghy L, Varga I, Matkovics B, Nagy J: Oxidative stress and antioxidant defense mechanism in glomerular diseases. Free Radic Biol Med 1997; 22:161-168.

          33. Massy ZA, Ma JZ, Louis TA, Kasiske BL. Lipid-lowering therapy in patients with renal disease. Kidney Int 1995; 48(1):188-198.

          34. Remuzzi G, Ruggenenti P, Benigni A: Understanding the nature of renal disease progression. Kidney Int 1997; 51:2-15.

          35. Noronha IL, Niemir Z, Stein H, Waldherr R: Cytokines and growth factors in renal disease. Nephrol Dial Transplant 1995; 10:775-786.

          36. Schiller B, Moran J: Focal glomerulosclerosis in the remnant kidney model-an inflammatory disease mediated by cytokines. Nephrol Dial Transplant 1997; 12:430-437.

          37. Kliem V, Johnson RJ, Alpers CE, Yoshimura A, Couser WG, Koch KM, Floege J: Mechanisms involved in the pathogenesis of tubulointerstitial fibrosis in 5/6-nephrectomized rats. Kidney Int 1996; 49:666-78.

          38. Isaka Y, Brees DK, Ikegaya K, Kaneda Y, Imai E, Noble NA, Border WA. Gene Tharapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney. Nat Med 1996; 2,(4):418-423.

          39. Kato S, Luyckx VA, Ots M, Lee K-W, Ziai F, Troy JL, Brenner BM, Mackenzie HS: Renin-angiotensin system blockade lowers MCP-1 expression in diabetic rats. Kidney Int 1999; 56:1037-1048.

          40. Johnston CI, Millar JA, McGrath BP, Matthews PG: Long-term effects of captopril (SQ14 225) on blood pressure and hormone levels in essential hypertension. Lancet 1979; 2:493-6.
          41. Turini GA, Brunner HR, Gribic M, Waeber B, Gavras H: Improvement of chronic congestive heart failure by oral captopril. Lancet 1979; 1213-1215.
          42. Anderson S, Meyer TW, Rennke HG, Brenner BM: Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. Journal of Clinical Investigation 1985; 76:612-9.
          43. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329:1456-62.
          44. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P: Effect of the angiotensin-converting-enzyme inhibitor benazeprol on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 1996; 334:939-945.
          45. NKF-DOQI Work Group. NKF-DOQI clinical practice guidelines. Am J Kidney Dis 1997;30,Suppl3


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