[32] Gleissner C, Galkina E, Nadler JL, Ley K. Mechanisms by which diabetes increases cardiovascular disease. Drug Discovery Today. Disease Mechanisms. 2007;**4**:131-140 [33] Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease a statement from the American Heart Association Councils on kidney in cardiovascular disease, high blood pressure research, clinical car-

[34] Stehouwer CDA, Smulders YM. Microalbuminuria and risk for cardiovascular disease: Analysis of potential mechanisms. Journal of the American Society of Nephrology:

diology, and epidemiology and prevention. Circulation. 2003;**108**:2154-2169

chronic kidney disease. European Heart Journal. 2010;**31**:2888-2896

chronic kidney disease. Kidney International. Supplement. 2012;**2**

Annals of Internal Medicine. 2001;**134**:629-636

American Society of Nephrology. 2005;**16**:3027-3037

Cleveland Clinic Journal of Medicine. 2008;**75**:705-713

analysis of controlled trials. Lancet. 2009;**373**:1009-1015

Kidney Diseases. 2010;**56**:1062-1071

of Nephrology. 2013;**24**:302-308

JASN. August 2006;**17**(8):2106-2111

S291-S334

[21] Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: The HOPE randomized trial. Annals of Internal Medicine. 2001;**134**:629-636

[7] Coresh J, Byrd-Holt D, Astor BC et al. Chronic kidney disease awareness, prevalence, and trends among US adults, 1999-2000. Journal of the American Society of Nephrology.

[8] Chadban SJ, Briganti EM, Kerr PG et al. Prevalence of kidney damage in Australian adults: The AusDiab kidney study. Journal of the American Society of Nephrology.

[9] Verhave JC, Gansevoort RT, Hillege HL et al, PREVEND Study Group. An elevated urinary albumin excretion predicts de novo development of renal function impairment in

[10] Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. New England Journal of Medicine. 2004;**23**:1296-1305

[11] Lainščak M. Cardiovascular Risk in Chronic Kidney Disease - eJIFCC 20/01; 2009. http://

[12] Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. Journal of the American Society of Nephrology. 1998;**9**:S16-S23

[13] McClellan WM, Langston RD, Presley R. Medicare patients with cardiovascular disease have a high prevalence of chronic kidney disease and a high rate of progression to endstage renal disease. Journal of the American Society of Nephrology. 2004;**15**:1912-1919

[14] Ridao N, Luno J, Garcia de Vinuesa S, Gómez, Valderrábano F. Prevalence of hypertension in renal disease. Nephrology, Dialysis, Transplantation. 2001;**16**(Suppl 1):70-73 [15] Morgado E, Neves PL. Hypertension and chronic kidney disease: cause and consequence therapeutic considerations. In: Babaei H, editor. Antihypertensive drugs. Rijeka: InTech;

[16] Lowrie EG, Huang WH, Lew NL, Liu Y. The relative contribution of measured variables to death risk among hemodialysis patients. In: Friedman E, editor, Death on Hemodialysis: Preventable or Inevitable? Hingham, MA: Kluwer Academic Publishers; 1994:121-141 [17] Agarwal R. Blood pressure components and the risk for end-stage renal disease and death in chronic kidney disease. Clinical Journal of the American Society of Nephrology.

[18] Kovesdy CP, Bleyer AJ, Molnar MZ, Ma JZ, Sim JJ, Cushman WC, Quarles LD, Kalantar-Zadeh K. Blood pressure and mortality in U.S. veterans with chronic kidney disease: A

[19] Foley RN, Parfrey PS, Harnett JD, Kr GM, Murray DC, Barre PE. Impact of hypertension on cardiomyopathy, morbidity and mortality in end-stage renal disease. Kidney

[20] Yuan J, Zou XR, Han SP, et al. Prevalence and risk factors for cardiovascular disease among chronic kidney disease patients: results from the Chinese cohort study of chronic

cohort study. Annals of Internal Medicine. 2013;**159**:233-242

kidney disease (C-STRIDE). BMC Nephrol. 2017;**18**:23

the general population. Kidney International. Supplement. 2004;**92**:S18-S21

2005;**16**:180-188

www.ifcc.org

2012:45-63

2009;**4**:830-837

International. 1996;**49**:1379-1385

2003;**14**(Suppl 2):S131-S138

94 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

[35] Schroijen MA, Dekkers OM, Grootendorst D, et al, and the NECOSAD Study Group. Survival in dialysis patients is not different between patients with diabetes as primary renal disease and patients with diabetes as a co-morbid condition. BMC Nephrology. 2011;**12**:69-76

predict coronary artery disease in hemodialysis patients. Journal of the American Society

Cardiovascular Risk Factors: The Old Ones and a Closer Look to the Mineral Metabolism

http://dx.doi.org/10.5772/intechopen.69323

97

[49] Tonelli M, Isles C, Curhan GC et al. Effect of pravastatin on cardiovascular events in

[50] Neves PL, Malho A, Cabrita A, et al. Statins and vitamin D: A friendly association in pre-

[51] Baigent C, Landray MJ, Reith, et al. The Effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease. (Study of Heart and Renal Protection): A randomised placebo-controlled trial. Lancet. 2011;**377**:

[52] Fellstrom BC, Jardine AG, Schmieder RE, et al, for the AURORA Study Group. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. New

[53] Wanner C, Kane V, Marz W, et al, for German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. New

[54] Guedes AM, Neves PL. Statins for renal patients: A fiddler on the roof? International

[55] KDIGO Guidelines. Pharmacological cholesterol-lowering treatment in adults. Kidney

[56] Di Lullo L, Gorini A, Russo D, Santoboni A, Ronco C. Left ventricular hypertrophy in chronic kidney disease patients: From pathophysiology to treatment. Cardiorenal

[57] Levy D, Anderson KM, Savage DD, Kannel WB, Christiansen JC, Castelli WP. Echocardiographically detected left ventricular hypertrophy: Prevalence and risk factors

[58] Parfrey S, Foley RN, Harnett JD, Kent GM, Murray DC, Barre PE. Outcome and risk factors for left ventricular disorders in chronic uraemia. Nephrology, Dialysis,

[59] Jerónimo T, Fragoso A, Mendes F, et al. Mineral metabolism and inflammation: Factors related to left ventricular hypertrophy in patients with diabetic nephropathy. Portuguese

[60] Ioannou K, Stel VS, Dounousi E, et al. Inflammation, endothelial dysfunction and increased left ventricular mass in chronic kidney disease (CKD) patients: a longitudinal

[61] Gutiérrez OM. Connecting the dots on fibroblast growth factor 23 and left ventricular

hypertrophy. Nephrology, Dialysis, Transplantation. 2016;**31**:1031-1033

The Framingham Heart Study. Annals of Internal Medicine. 1988;**108**:7-13

people with chronic kidney disease. Circulation. 2004;**110**:1557-1563

England Journal of Medicine. 2009;**360**:1395-1407

England Journal of Medicine. 2005;**353**:238-248

International Supplement. 2013;**3**:271-279

Medicine. 2015;**5**:254-266

Transplantation. 1996;**11**:1277-1285

study. PLoS One **10**:e0138461

Journal of Nephrology. 2012;**2012**. DOI: 10.1155/2012/806872

Journal of Nephrology & Hypertension. 2016;**30**:121-131

dialysis patients. International Urology and Nephrology. 2010;**42**:173-179

of Nephrology. 1997;**8**:1889-1898

2181-2192

predict coronary artery disease in hemodialysis patients. Journal of the American Society of Nephrology. 1997;**8**:1889-1898

[49] Tonelli M, Isles C, Curhan GC et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation. 2004;**110**:1557-1563

[35] Schroijen MA, Dekkers OM, Grootendorst D, et al, and the NECOSAD Study Group. Survival in dialysis patients is not different between patients with diabetes as primary renal disease and patients with diabetes as a co-morbid condition. BMC Nephrology.

[36] Fang W, Yang X, Kothari J, et al. Patient and technique survival of diabetics on peritoneal dialysis: One-center's experience and review of the literature. Clinical Nephrology.

[37] United States Renal Data System. American Journal of Kidney Diseases. 2010;**55**(Suppl 1)

[38] Lewis EJ, Husincker LG, Bain RP, et al, for the the Collaborative Study Group. The effect of angiotensin-converting-enzyme inhibitor on diabetic nephropathy. The New England

[39] Lewis EJ, Hunsicker LG, Clarke WR, et al, for the Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due

[40] Shurraw S, Tonelli M. Statins for treatment of dyslipidemia in chronic kidney disease.

[41] Tsimihodimos V, Mitrogianni Z, Elisaf M. Dyslipidemia associated with chronic kidney

[42] Ross R. Atherosclerosis: An inflammatory disease. New England Journal of Medicine.

[43] Mimic-Oka J, Simic T, Pljesa M. Oxidative modifications of plasma proteins in different

[44] Stenvinkel P, Heimburger O, Lindholm B, Kaysen GA, Bergstrom J. Are two types of malnutrition in chronic renal failure? Evidence of relationship between malnutrition, inflammation and atherosclerosis (MIA syndrome). Neprol Dial Transplant. 2000;**15**:953-960

[45] Kalantar-Zadeh K, Block G, Humphreys MH, Kopple JD. Reverse epidemiology of cardiovascular risk factors in maintenance dialysis patients. Kidney International. 2003;**63**:

[46] Lowrie EG, Lew NL. Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities.

[47] Iseki K, Yamazato M, Tozawa M, Takishita S. Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients. Kidney International.

[48] Koch M, Kutkuhn B, Trenkwalder E, Bach D, Grabensee B, Dieplinger H, Kronenberg F. Apolipoprotein B, fibrinogen, HDL cholesterol, and apolipoprotein(a) phenotypes

to type 2 diabetes. New England Journal of Medicine. 2001;**345**:851-860

disease. Open Cardiovascular Medicine Journal. 2011;**5**:41-48

stages of kidney failure. Medicine and Biology. 2001;**8**:1-5

American Journal of Kidney Diseases. 1990;**15**:458-482

2011;**12**:69-76

2008;**69**:193-200

1999;**340**:115-126

793-808

2002;**61**:1887-1893

Journal of Medicine. 1993;**329**:1456-1462

96 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Peritoneal Dialysis International. 2006;**26**:523-539

[62] Neves PL, Silva AP, Bernardo I. Elderly patients in chronic hemodialysis: Risk factors for left ventricular hypertrophy. American Journal of Kidney Diseases. 1997;**30**:224-228

[75] Narang R, Ridout D, Nonis C, Kooner JS. Serum calcium, phosphorus and albumin levels in relation to the angiographic severity of coronary artery disease. International

Cardiovascular Risk Factors: The Old Ones and a Closer Look to the Mineral Metabolism

http://dx.doi.org/10.5772/intechopen.69323

99

[76] Rasouli M, Kiasari AM. Serum calcium and phosphorus associate with the occurrence and severity of angiographically documented coronary heart disease, possibly through correlation with atherogenic (apo)lipoproteins. Clinical Chemistry and Laboratory

[77] Ruan L, Chen, Srinivasan SR, Xu J, Toprak A, Berenson GS. Relation of serum phosphorus levels to carotid intima-media thickness in asymptomatic young adults (from the

[78] Onufrak SJ, Bellasi A, Shaw LJ, et al. Phosphorus levels are associated with subclinical

[79] Saab G, Whooley MA, Schiller NB, Ix JH. Association of serum phosphorus with left ventricular mass in men and women with stable cardiovascular disease: Data from the

[80] Kendrick J, Kestenbaum B, Chonchol M. Phosphate and cardiovascular disease.

[81] El-Abbadi MM, Pai AS, Leaf EM, et al. Phosphate feeding induces arterial medial calcification in uremic mice: Role of serum phosphorus, fibroblast growth factor-23, and

[82] Amann K, Ritz E, Wiest G et al. A role of parathyroid hormone for the activation of cardiac fibroblasts in uremia. Journal of the American Society of Nephrology. 1994;**4**:1814-1819

[83] Rostand SG, Drüeke TB. Parathyroid hormone, vitamin D, and cardiovascular disease in

[84] Jono S, Nishizawa Y, Shioi A, Morii H. Parathyroid hormone–related peptide as a local regulator of vascular calcification: Its inhibitory action on in vitro calcification by bovine vascular smooth muscle cells. Arteriosclerosis, Thrombosis, and Vascular Biology.

[85] Jono S, McKee M, Shioi A, Nishizawa Y, Mori K, et al. Phosphate regulation of vascular

[86] Graciolli FG, Neves KR, dos Reis LM, et al. Phosphorus overload and PTH induce aortic expression of Runx2 in experimental uraemia. Nephrology, Dialysis, Transplantation.

[87] Moe SM, O'Neill KD, Duan D, et al. Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins. Kidney International. 2002;**61**:638-647

[88] Shuto E, Taketani Y, Tanaka R, et al. Dietary phosphorus acutely impairs endothelial

function. Journal of the American Society of Nephrology. 2009;**20**:1504-1512

smooth muscle cell calcification. Circulation Research. 2000;**87**:e10-e17

Bogalusa Heart Study). American Journal of Cardiology. 2010;**106**(6):793-797

atherosclerosis in the general population. Atherosclerosis. 2008;**199**:424-431

Heart and Soul Study. American Journal of Kidney Disease. 2010;**56**:496-505

Advances in Chronic Kidney Disease. 2011;**18**:113-119

osteopontin. Kidney International. 2009;**75**:1297-1307

chronic renal failure. Kidney. International. 1999;**56**:383-392

Journal of Cardiology. 1997;**60**:73-79

Medicine. 2006;**44**(1):43-50

1997;**17**:1135-1142

2009;**24**:1416-1421

[75] Narang R, Ridout D, Nonis C, Kooner JS. Serum calcium, phosphorus and albumin levels in relation to the angiographic severity of coronary artery disease. International Journal of Cardiology. 1997;**60**:73-79

[62] Neves PL, Silva AP, Bernardo I. Elderly patients in chronic hemodialysis: Risk factors for left ventricular hypertrophy. American Journal of Kidney Diseases. 1997;**30**:224-228

[63] Ruzicka M, Leenen FHH. Hypertensive therapy in dialysis patients. Seminars in Dialysis.

[64] Covic A, Mardare NG, Ardeleanu S, Prisada O, Gusbeth-Tatomir P, Goldsmith DJ. Serial echocardiographic changes in patients on hemodialysis: An evaluation of guideline

[65] Culleton BF, Walsh M, Klarenbach SW, et al. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: A randomized

[66] London GM, Pannier B, Guerin AP, et al. Alterations of left ventricular hypertrophy in and survival of patients receiving hemodialysis: Follow-up of an interventional study.

[67] Block G A, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphorus product with mortality risk in chronic hemodialysis patients:

[68] Tentori F, Blayney MJ, Albert JM et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: The Dialysis Outcomes and Practice

Patterns Study (DOPPS). American Journal of Kidney Diseases. 2008;**52**:519-530

[69] Tonelli M, Sacks F, Pfeffer M et al. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation. 2005;**112**:2627-2633

[70] Dhingra R, Sullivan LM, Fox CS et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Archives of Internal

[71] Foley RN, Collins AJ, Ishani A, et al. Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: The Atherosclerosis Risk in Communities (ARIC)

[72] Jung HH, Kim SW, Han H. Inflammation, mineral metabolism and progressive coronary artery calcification in patients on haemodialysis. Nephrology, Dialysis, Transplantation.

[73] Adeney KL, Siscovick DS, Ix JH et al. Association of serum phosphate with vascular and valvular calcification in moderate CKD. Journal of the American Society of Nephrology.

[74] Kannel WB, Wolf PA, Garrison RJ. Monograph Section 34: Some Risk Factors Related to the Annual Incidence of Cardiovascular Disease and Death Using Pooled Repeated Biennial Measurements: Framingham Heart Study, 30-Year Followup. Springfield, Mass:

implementation. Journal of Nephrology. 2006;**19**:783-793

Journal of the American Society of Nephrology. 2001;**12**:2759-2767

A national study. American Journal of Kidney Diseases. 1998;**31**:607-617

controlled trial. JAMA. 2007;**298**:1291-1299

98 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Medicine. 2007;**167**:879-885

2006;**21**:1915-1920

2009;**20**:381-387

Study. American Heart Journal. 2008;**156**:556-563

National Technical Information Service; 1987. pp. 1-459

1994;**3**:176-178

[89] Di Marco GS, König M, Stock C, et al. High phosphate directly affects endothelial function by downregulating annexin II. Kidney International 2013;**83**:213-222

[104] Kiechl S, Werner P, Knoflach M, Furtner M, Willeit J, Schett G. The osteoprotegerin/ RANK/RANKL system: A bone key to vascular disease. Expert Review of Cardiovascular

Cardiovascular Risk Factors: The Old Ones and a Closer Look to the Mineral Metabolism

http://dx.doi.org/10.5772/intechopen.69323

101

[105] Kiechl S, Schett G, Schwaiger J, et al. Soluble receptor activator of nuclear factor-ligand

[106] Krivosíková Z, Spustová V, Stefíková K, Dzúrik R. The influence of vitamin D supplementation on OPG/RANKL/RANK system in postmenopausal women: The six month

[107] HofBauer LC, Kühne CA, Viereck V. The OPG/RANKL/RANK system in metabolic bone disease. Journal of Musculoskeletal & Neuronal Interactions. 2004;**4**:268-275 [108] Scragg R. Seasonality of cardiovascular disease mortality and the possible protective effect of ultra-violet radiation. International Journal of Epidemiology. 1981;**10**:337-341

[109] Fabsitz R, Feinleib M. Geographic patterns in county mortality rates from cardiovascu-

[110] Smith WC, Tunstall-Pedoe H. European regional variation in cardiovascular mortality.

[111] Giovannucci E, Liu Y, Hollis BW et al. 25-hydroxyvitamin D and risk of myocardial infarction in men: A prospective study. Archives of Internal Medicine. 2008;**168**:1174-1180

[112] Dobnig H, Pilz S, Scharnagl H et al. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxy VD levels with all-cause and cardiovascular mortality.

[113] Wang L, Song Y, Manson JE et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: A meta-analysis of prospective studies. Circulation. Cardiovascular

[114] Grandi NC, Breitling LP, Brenner H. Vitamin D and cardiovascular disease: Systematic review and meta-analysis of prospective studies. Preventive Medicine. 2010;**51**:228-233

[115] Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: The PRIMO

[116] Wu J, Garami M, Cheng T et al. 1,25(OH)2 VD3, and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes. Journal of Clinical

[117] Meems LM, Cannon MV, Mahmud H et al. The vitamin D receptor activator paricalcitol prevents fibrosis and diastolic dysfunction in a murine model of pressure overload.

[118] Oliveira RB, Moysés RMA. FGF-23: State of the art. Jornal Brasileiro de Nefrologia.

Journal of Steroid Biochemistry and Molecular Biology. 2012;**132**:282-289

and risk for cardiovascular disease. Circulation. 2007;**116**:385-391

lar diseases. American Journal of Epidemiology. 1980;**111**:315-328

Therapy. 2006;**4**:801-811

clinical study. Bone. 2006;**38**:S27

British Medical Bulletin. 1984;**40**:374-379

Quality and Outcomes. 2012;**5**:819-829

Investigation. 1996;**97**:1577-1588

2010;**32**:323-331

Archives of Internal Medicine. 2008;**168**:1340-1349

randomized controlled trial. JAMA. 2012;**307**:674-684

[104] Kiechl S, Werner P, Knoflach M, Furtner M, Willeit J, Schett G. The osteoprotegerin/ RANK/RANKL system: A bone key to vascular disease. Expert Review of Cardiovascular Therapy. 2006;**4**:801-811

[89] Di Marco GS, König M, Stock C, et al. High phosphate directly affects endothelial func-

[90] Maizel J, Six I, Dupont S, et al. Effects of sevelamer treatment on cardiovascular abnormalities in mice with chronic renal failure. Kidney International 2013;**84**:491-500 [91] Mathew S, Lund RJ, Strebeck F, Tustison KS, Geurs T, Hruska KA. Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy. Journal of the American Society of Nephrology.

[92] Van TV, Watari E,Taketani Y, et al. Dietary phosphate restriction ameliorates endothelial dysfunction in adenine-induced kidney disease rats. Journal of Clinical Biochemistry

[93] Ahn J, Yu K, Stolzenberg-Solomon R, et al. Genome-wide association study of circulat-

[94] Bachschmid MM, Van der loo B. A new sunshine in the vasculature. Circulation.

[95] Weishaar RE, Simpson RU. Involvement of vitamin D3 with cardiovascular function, II: Direct and indirect effects. American Journal of Physiology. 1987;**253**:E675-E683 [96] Hochhauser E, Barak J, Kushnir T, Navon G, Meyer MS, Edelstein S, Ben Bassat MB, Vidne BA. Mechanical, biochemical, and structural effects of vitamin D deficiency on

[97] O'Connell TD, Berry JE, Jarvis AK, Somerman MJ, Simpson RU.1,25-dihydroxyvitamin D3 regulation of cardiac myocyte proliferation and hypertrophy. American Journal of

[98] Wakasugi M, Noguchi T, Inoue M, Kazama Y, Tawata M, Kanemaru Y Onaya T. Vitamin D3 stimulates the production of prostacyclin by vascular smooth muscle cells.

[99] Wu J, Garami M, Cao L, Li Q, Gardner DG. 1,25(OH)2D3 suppresses expression and secretion of atrial natriuretic peptide from cardiac myocytes. American Journal of

[100] Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and vitamin D deficiency into perspective. The British Journal of Nutrition. 2005;**94**:483-492 [101] Smogorzewski M, Perna AF, Borum PR, Massry SG. Fatty acid oxidation in the myocardium: Effects of parathyroid hormone and CRF. Kidney International. 1988;**34**:797-803

[102] Pfeilschifter J, Lauhuf F, Müller-Beckmann B, Blum WF, Pfistr T, Ziegler R. Parathyroid hormone increases the concentration of insulin-like growth factor-I and transforming growth factor beta 1 in rat bone. Journal of Clinical Investigation. 1995;**96**:767-774 [103] Artaza JN, Mehrotra R, Norris KC. Vitamin D and the cardiovascular system. CJASN.

Physiology - Heart and Circulatory Physiology. 1997;**272**:H1751-H1758

ing vitamin D levels. Human Molecular Genetics. 2010;**19**(13):2739-2745

tion by downregulating annexin II. Kidney International 2013;**83**:213-222

2007;**18**:122-130

2005;**111**:1571-1573

and Nutrition. 2012;**51**:27-32

100 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

the chick heart. Angiology. 1989;**40**:300-308

Prostaglandins. 1991;**42**:127-136

Physiology. 1995;**268**:E1108-E1113

2009 September;**4**(9):1515-1522

[119] Quarles LD. Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nature Reviews Endocrinology. 2012;**8**:276-286

[134] Mirza MA, Hansen T, Johansson L, et al. Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrology, Dialysis, Transplantation.

Cardiovascular Risk Factors: The Old Ones and a Closer Look to the Mineral Metabolism

http://dx.doi.org/10.5772/intechopen.69323

103

[135] Parker BD, Schurgers LJ, Brandenburg VM, et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: The Heart and Soul Study. Annals of Internal Medicine. 2010;**152**(10):640-648 [136] Liabeuf S, Okazaki H, Desjardins L, et al. Vascular calcification in chronic kidney disease: Are biomarkers useful for probing the pathobiology and the health risks of this process in the clinical scenario? Nephrology, Dialysis, Transplantation. 2014;**29**(7):1275-1284 [137] Zhang M, Yan J, Zhu M , Ni Z. Fibroblast growth factor 23 predicts coronary calcification and poor prognosis in patients with chronic kidney disease stages 3-5D. Annals of

[138] Price PA, Lim JE. The inhibition of calcium phosphate precipitation by fetuin is accompanied by the formation of a fetuin-mineral complex. Journal of Biological Chemistry.

[139] Roos, M, Lutz, J, Salmhofer, H, et al, Relation between plasma fibroblast growth factor-23, serum fetuin-A levels and coronary artery calcification evaluated by multislice computed tomography in patients with normal kidney function. Clinical Endocrinology.

[140] Scialla JJ, Lau WL, Reilly MP, et al. Chronic Renal Insufficiency Cohort Study Investigators. Fibroblast growth factor 23 is not associated with and does not induce

[141] Fukino K, Suzuki T, Saito Y, et al. Regulation of angiogenesis by the aging suppressor gene klotho. Biochemical and Biophysical Research Communications. 2002;**293**:332-337

[142] Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, et al. Suppression of aging in mice by the hormone Klotho. Science. 2005 Sep 16;**309**(5742):1829-1833 [143] Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochemical and Biophysical Research Communications. 1998 Jan 26;**242**(3):

[144] Kuro-o M. Overview of the FGF23-Klotho axis. Pediatric Nephrology. 2010 Apr;**25**(4):

[145] Shroff R and Shanahan MC. Klotho: An elixir of youth for the vasculature? Journal of

[146] Erben RG. Update on FGF23 and Klotho signaling. Molecular and Cellular Endocri-

[147] Kuro-o M. Klotho and aging. Biochimica et Biophysica Acta. 2009;**1790**(10):1049-1058 [148] Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. Journal of the American Society of Nephrology: JASN. 2011;**22**(1):124-136

arterial calcification. Kidney International. 2013;**83**(6):1159-1168

2009;**24**(10):3125-3131

2003;**278**:22144-22152

2008;**68**:660-665

626-630

583-590. PubMed PMID: 19626341

nology. 2016;**432**:56-65

the American Society of Nephrology. 2011;**22**:5-7

Clinical and Laboratory Science. 2015;**45**(1):17-22

[134] Mirza MA, Hansen T, Johansson L, et al. Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrology, Dialysis, Transplantation. 2009;**24**(10):3125-3131

[119] Quarles LD. Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabo-

[120] Kestenbaum B, Sachs MC, Hoofnagle AN, et al. Fibroblast growth factor-23 and cardiovascular disease in the general population: The Multi-Ethnic Study of Atherosclerosis.

[121] Wolf M. Forging forward with 10 burning questions on FGF23 in kidney disease.

[122] Tuñón J, Cristóbal C, Tarín N et al. Coexistence of low vitamin D and high fibroblast growth factor-23 plasma levels predicts an adverse outcome in patients with coronary

[123] Burnett SM, Gunawardene SC, Bringhurst FR, Jüppner H, Lee H, Finkelstein JS. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. Journal of Bone

[124] Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. Journal of Clinical Endocrinology

[125] Hasegawa H, Nagano N, Urakawa I, et al. Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with

[126] Wahl P, Wolf M. FGF23 in chronic kidney disease. Advances in Experimental Medicine

[127] Drüeke TB, Massy ZA. Circulating Klotho levels: Clinical relevance and relationship

[128] Aline Martin A, Valentin David,L. Darryl Quarles. Regulation and function of the FGF23/Klotho endocrine pathways. Physiological Reviews. 2012;**92**:131-155

[129] Touchberry CD, Green TM, Tchikrizov V, et al. FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. American

[130] Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. New England Journal of Medicine.

[131] Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrology,

[132] Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy.

[133] Wyatt CM and Drueke TB. Fibroblast growth factor receptor 4: The missing link between chronic kidney disease and FGF23-induced left ventricular hypertrophy? Kidney

Journal of Physiology, Endocrinology and Metabolism. 2013;**304**:E863-E873

early-stage chronic kidney disease. Kidney International. 2010;**78**:975-980

with tissue Klotho expression. Kidney International. 2013;**83**(19):13-15.

Journal of the American Society of Nephrology. 2010;**21**:1427-1435

lism. Nature Reviews Endocrinology. 2012;**8**:276-286

Circulation. Heart Failure. 2014;**7**:409-417

102 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

artery disease. PLoS One. 2014;**9**:e95402

and Mineral Research. 2006;**21**:1187-1196

and Metabolism. 2006 Aug;**91**(8):3144-3149

Dialysis, Transplantation. 2009;**24**:2792-2796

Journal of Clinical Investigation. 2011;**121**:4393-4408

and Biology. 2012;**728**:107-125

2008;**359**:584-592

International. 2016;**89**:7-9

[149] Xie J, Yoon J, An SW, Kuro-o M, Huang CL. Soluble klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. Journal of the American Society of Nephrology. 2015 May;**26**(5):1150-1160

**Chapter 5**

**Provisional chapter**

**Cardiovascular Aspects of Patients with Chronic Kidney**

Chronic kidney disease (CKD) is a globally recognized public health concern. Multiple studies have shown the association of CKD with cardiovascular mortality that persists after adjustment for traditional cardiovascular disease (CVD) risk factors. CKD causes accelerated coronary artery disease (CAD). In this chapter, we discuss the pathophysi‐ ological mechanisms that play a role in increasing CVD risk in patients with CKD. Further we delve into some commonly encountered challenges related to CVD in patients with CKD. These include revascularization challenges, contrasted induced nephropathy and alterations in traditional risk factors for CVD in renal transplant

**Keywords:** coronary artery disease, chronic kidney disease, mortality, morbidity, public

Chronic kidney disease (CKD) is recognized as a major global public health problem [1]. It is estimated that 10–25% of population from Asia, Australia, Europe and United States of

Multiple studies have shown the association of CKD with cardiovascular mortality that persists after adjustment for traditional cardiovascular disease (CVD) risk factors. These include the Atherosclerosis Risk in Communities study (ARIC) and the Cardiovascular

**Cardiovascular Aspects of Patients with Chronic Kidney**

DOI: 10.5772/intechopen.69294

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Disease and End-Stage Renal Disease**

**Disease and End-Stage Renal Disease**

Hashim Hussnain Ahmed, Subodh Devabhaktuni, Edward Co, Arhama Aftab Malik, Syed Shah and

Hashim Hussnain Ahmed, Subodh Devabhaktuni, Edward Co, Arhama Aftab Malik, Syed Shah and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Ali Osama Malik, Sumit Sehgal,

Ali Osama Malik, Sumit Sehgal,

http://dx.doi.org/10.5772/intechopen.69294

Chowdhury Ahsan

**Abstract**

patients.

health

**1. Introduction**

America (USA) is affected by CKD [2–6].

Chowdhury Ahsan

**Provisional chapter**

## **Cardiovascular Aspects of Patients with Chronic Kidney Disease and End-Stage Renal Disease Disease and End-Stage Renal Disease**

**Cardiovascular Aspects of Patients with Chronic Kidney**

DOI: 10.5772/intechopen.69294

Ali Osama Malik, Sumit Sehgal, Hashim Hussnain Ahmed, Subodh Devabhaktuni, Edward Co, Arhama Aftab Malik, Syed Shah and Chowdhury Ahsan Hashim Hussnain Ahmed, Subodh Devabhaktuni, Edward Co, Arhama Aftab Malik, Syed Shah and Chowdhury Ahsan Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69294

Ali Osama Malik, Sumit Sehgal,

#### **Abstract**

[149] Xie J, Yoon J, An SW, Kuro-o M, Huang CL. Soluble klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. Journal of

[150] Xie J, Cha SK, An SW, Kuro-O M, Birnbaumer L, Huang CL, Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nature Communications.

[151] Hu MC, Shi M, Cho HJ, et al. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. American Society of Nephrology. 2015;**26**(6):1290-1302 [152] Floege J, Fliser D.Klotho Deficiency and the cardiomyopathy of advanced CKD. Journal

the American Society of Nephrology. 2015 May;**26**(5):1150-1160

104 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

of the American Society of Nephrology. 2015;**26**:1229-1237

2012;**3**:1238

Chronic kidney disease (CKD) is a globally recognized public health concern. Multiple studies have shown the association of CKD with cardiovascular mortality that persists after adjustment for traditional cardiovascular disease (CVD) risk factors. CKD causes accelerated coronary artery disease (CAD). In this chapter, we discuss the pathophysi‐ ological mechanisms that play a role in increasing CVD risk in patients with CKD. Further we delve into some commonly encountered challenges related to CVD in patients with CKD. These include revascularization challenges, contrasted induced nephropathy and alterations in traditional risk factors for CVD in renal transplant patients.

**Keywords:** coronary artery disease, chronic kidney disease, mortality, morbidity, public health

## **1. Introduction**

Chronic kidney disease (CKD) is recognized as a major global public health problem [1]. It is estimated that 10–25% of population from Asia, Australia, Europe and United States of America (USA) is affected by CKD [2–6].

Multiple studies have shown the association of CKD with cardiovascular mortality that persists after adjustment for traditional cardiovascular disease (CVD) risk factors. These include the Atherosclerosis Risk in Communities study (ARIC) and the Cardiovascular

Health Study [7–9]. The risk of developing congestive heart failure, atrial fibrillation, stroke, coronary artery disease (CAD) and peripheral artery disease (PAD) is increased twofold in patients with glomerular filtration rate (eGFR) < 70ml/min/1.73m<sup>2</sup> [8, 10]. Furthermore, in two separate meta‐analyses of twenty‐one studies from fourteen different countries eGFR and albuminuria were found to be independently associated with increased risk of all‐cause and cardiovascular mortality [11, 12].

**2.2. Albuminuria a marker of worse cardiovascular outcomes in CKD patients**

albuminuria have been reported in other large scale studies [11, 12].

**3. Ischemic heart disease in chronic kidney disease**

**3.1. Background**

higher in the CKD population [24].

factor for developing CVD [30].

**3.2. Revascularization in CKD patients with stable CAD**

trials, the efficacy of these agents in patients with CKD is still unclear.

Abuminuria has been proven to be a significant risk factor for all cause and CVD related mor‐ tality in patients with CKD. Pooled data from Van der Welde et al., demonstrated a significant increase in cardiovascular mortality in patients with Albumin‐to‐creatinine ratio of 10 mg/dl compared to 5 mg/dl [22]. Similar results demonstrating an association of CVD mortality with

Cardiovascular Aspects of Patients with Chronic Kidney Disease and End-Stage Renal Disease

http://dx.doi.org/10.5772/intechopen.69294

107

Cardiovascular (CV) mortality is the leading cause of death in CKD patients and the risk of CV mortality increases with decrease in eGFR. Most of the burden of CV mortality in CKD patients is secondary to ischemic heart disease or complications associated with it including congestive heart failure. The severity and incidence of CAD increases as the kidney function declines with the prevalence of multi‐vessel CAD and left main disease being significantly

Coronary arteries in CKD patients have shown to exhibit more extensive atherosclerosis [25]. Multiple studies have shown the association of CKD with cardiovascular mortality that persists after adjustment for traditional cardiovascular disease (CVD) risk factors [26, 27]. Mineralocorticoid excess, oxidative stress and cellular inflammation are linked to plaque for‐ mation and rupture in CKD patients. Vitamin D deficiency a common sequela of CKD could explain the propensity of CKD patients to develop CAD. It has been shown that patients with Vitamin D deficiency have higher risk of myocardial infarction (MI). Similarly fibroblast growth factor 23 (FGF 23) a hormone usually elevated in CKD patients, to mitigate hyper‐ phosphatemia was associated with increased CVD mortality in patients with CKD [28, 29].

In summation, the pathophysiological basis of increased CVD risk and severity in patients with CKD is due to a complex interplay of factors involving hormonal and immune mediated responses. However the risk of CAD in CKD has been well established. Hence in 2013 the American Heart Association (AHA) issued a statement to classify CKD as an independent risk

Management of patients with established CAD and CKD is challenging. Medical manage‐ ment in patients with renal dysfunction has been based on therapy shown to be beneficial in patient population without CKD. These medications include aspirin, beta‐blockers, nitrates, hydroxymethylglutaryl co‐enzyme A reductase inhibitors (statins) and angiotensin convert‐ ing enzyme inhibitors. However because of routine exclusion of CKD patients from clinical

In this chapter we discuss the acute and chronic cardiovascular impact of patients with reduced kidney function. We further delve in evaluation of coronary artery disease in patients with CKD. We also address the cardiovascular aspects of patient care in renal transplant patients including modification of traditional CVD risk factors in patients taking immuno‐ suppressive therapy.

## **2. Epidemiology**

CKD is a globally recognized public health burden [13]. USA alone deals with a population of more than 20 million people with CKD [14]. Data from other developed and developing nations confirms the rising trend of the disease. Data from China estimates this number to be close to 100 million Chinese being affected with CKD [15].

CKD has long shared its associations with CVD. The prevalence of CVD among patients with CKD has been known across trials in USA, Japan, Spain, United Kingdom and, recently, across China. Highest prevalence was found in U.K., 47.2% followed by Spain, 39.1%, U.S., 33.4%, Japan, 26.8% and China 9.8% [16–19].

United States Renal Data System (USRDS) reports from 2016 revealed the prevalence of any cardiovascular event to be twice among those with CKD compared to those without it, 68.8% vs. 34.1% respectively.

## **2.1. Linear relationship of cardiovascular mortality with EGFR**

CKD is an independent risk factor for progression to cardiovascular disease, known to con‐ tribute to cardiovascular morbidity and mortality [20]. Go et al., using longitudinal measure‐ ment of estimated eGFR, demonstrated the inverse relationship between eGFR and mortality rate secondary to cardiovascular events, below an eGFR of 60 ml/min per 1.73 m<sup>2</sup> [21]. A meta‐ analysis from 2011, comprising a grand total of 266,975 patients reported an exponential rise in mortality with eGFR below 60 ml/min per 1.73 m<sup>2</sup> [22]. (21,307,840) For cardiovascular mor‐ tality, adjusted hazard ratios at eGFR 60, 45, and 15 ml/min per 1.73 m<sup>2</sup> were 1.11 (0.93–1.32), 1.73 (1.49–2.00), and 3.08 (1.89–5.01), respectively [22].

Manjunath et al., also demonstrated eGFR as an independent risk factor for progression to CVD [23]. In a sample population of 4893, subjects with GFR 90 mL/min/1.73 m<sup>2</sup> had a 15% risk of CVD over 3 years while subjects with GFR 30 mL/min/1.73 m<sup>2</sup> had a 40% risk of CVD [23]. These findings were independent from traditional risk factors of cardiovascular diseases.

## **2.2. Albuminuria a marker of worse cardiovascular outcomes in CKD patients**

Abuminuria has been proven to be a significant risk factor for all cause and CVD related mor‐ tality in patients with CKD. Pooled data from Van der Welde et al., demonstrated a significant increase in cardiovascular mortality in patients with Albumin‐to‐creatinine ratio of 10 mg/dl compared to 5 mg/dl [22]. Similar results demonstrating an association of CVD mortality with albuminuria have been reported in other large scale studies [11, 12].

## **3. Ischemic heart disease in chronic kidney disease**

## **3.1. Background**

Health Study [7–9]. The risk of developing congestive heart failure, atrial fibrillation, stroke, coronary artery disease (CAD) and peripheral artery disease (PAD) is increased twofold in

separate meta‐analyses of twenty‐one studies from fourteen different countries eGFR and albuminuria were found to be independently associated with increased risk of all‐cause and

In this chapter we discuss the acute and chronic cardiovascular impact of patients with reduced kidney function. We further delve in evaluation of coronary artery disease in patients with CKD. We also address the cardiovascular aspects of patient care in renal transplant patients including modification of traditional CVD risk factors in patients taking immuno‐

CKD is a globally recognized public health burden [13]. USA alone deals with a population of more than 20 million people with CKD [14]. Data from other developed and developing nations confirms the rising trend of the disease. Data from China estimates this number to be

CKD has long shared its associations with CVD. The prevalence of CVD among patients with CKD has been known across trials in USA, Japan, Spain, United Kingdom and, recently, across China. Highest prevalence was found in U.K., 47.2% followed by Spain, 39.1%, U.S.,

United States Renal Data System (USRDS) reports from 2016 revealed the prevalence of any cardiovascular event to be twice among those with CKD compared to those without it, 68.8%

CKD is an independent risk factor for progression to cardiovascular disease, known to con‐ tribute to cardiovascular morbidity and mortality [20]. Go et al., using longitudinal measure‐ ment of estimated eGFR, demonstrated the inverse relationship between eGFR and mortality

analysis from 2011, comprising a grand total of 266,975 patients reported an exponential rise

Manjunath et al., also demonstrated eGFR as an independent risk factor for progression to

These findings were independent from traditional risk factors of cardiovascular diseases.

rate secondary to cardiovascular events, below an eGFR of 60 ml/min per 1.73 m<sup>2</sup>

CVD [23]. In a sample population of 4893, subjects with GFR 90 mL/min/1.73 m<sup>2</sup>

tality, adjusted hazard ratios at eGFR 60, 45, and 15 ml/min per 1.73 m<sup>2</sup>

of CVD over 3 years while subjects with GFR 30 mL/min/1.73 m<sup>2</sup>

[8, 10]. Furthermore, in two

[21]. A meta‐

had a 15% risk

were 1.11 (0.93–1.32),

had a 40% risk of CVD [23].

[22]. (21,307,840) For cardiovascular mor‐

patients with glomerular filtration rate (eGFR) < 70ml/min/1.73m<sup>2</sup>

106 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

close to 100 million Chinese being affected with CKD [15].

**2.1. Linear relationship of cardiovascular mortality with EGFR**

in mortality with eGFR below 60 ml/min per 1.73 m<sup>2</sup>

1.73 (1.49–2.00), and 3.08 (1.89–5.01), respectively [22].

33.4%, Japan, 26.8% and China 9.8% [16–19].

cardiovascular mortality [11, 12].

suppressive therapy.

**2. Epidemiology**

vs. 34.1% respectively.

Cardiovascular (CV) mortality is the leading cause of death in CKD patients and the risk of CV mortality increases with decrease in eGFR. Most of the burden of CV mortality in CKD patients is secondary to ischemic heart disease or complications associated with it including congestive heart failure. The severity and incidence of CAD increases as the kidney function declines with the prevalence of multi‐vessel CAD and left main disease being significantly higher in the CKD population [24].

Coronary arteries in CKD patients have shown to exhibit more extensive atherosclerosis [25]. Multiple studies have shown the association of CKD with cardiovascular mortality that persists after adjustment for traditional cardiovascular disease (CVD) risk factors [26, 27]. Mineralocorticoid excess, oxidative stress and cellular inflammation are linked to plaque for‐ mation and rupture in CKD patients. Vitamin D deficiency a common sequela of CKD could explain the propensity of CKD patients to develop CAD. It has been shown that patients with Vitamin D deficiency have higher risk of myocardial infarction (MI). Similarly fibroblast growth factor 23 (FGF 23) a hormone usually elevated in CKD patients, to mitigate hyper‐ phosphatemia was associated with increased CVD mortality in patients with CKD [28, 29].

In summation, the pathophysiological basis of increased CVD risk and severity in patients with CKD is due to a complex interplay of factors involving hormonal and immune mediated responses. However the risk of CAD in CKD has been well established. Hence in 2013 the American Heart Association (AHA) issued a statement to classify CKD as an independent risk factor for developing CVD [30].

## **3.2. Revascularization in CKD patients with stable CAD**

Management of patients with established CAD and CKD is challenging. Medical manage‐ ment in patients with renal dysfunction has been based on therapy shown to be beneficial in patient population without CKD. These medications include aspirin, beta‐blockers, nitrates, hydroxymethylglutaryl co‐enzyme A reductase inhibitors (statins) and angiotensin convert‐ ing enzyme inhibitors. However because of routine exclusion of CKD patients from clinical trials, the efficacy of these agents in patients with CKD is still unclear.

No robust evidence is yet available to ascertain whether CKD patients with chronic stable angina who undergo revascularization have a definite survival advantage compared to CKD patients on medical therapy alone. In the only randomized study of dialysis patients compar‐ ing invasive approach (PCI and coronary artery bypass graft surgery (CABG)) with medical therapy alone, the invasive approach had a clear survival benefit [31]. However medical therapy at that time only consisted of calcium channel blockers, and use of other agents proven to have survival advantage in patients with cardiovascular disease was not the norm. Furthermore, this study only included patients with diabetes mellitus. In another study done in 2002, PCI did not significantly improve survival [32].

and other comorbid conditions [46]. However in analysis of CREDO‐Hyoto PCI/CABG reg‐ istry Marui A et al. found CABG relative to PCI reduced risk of cardiac death, sudden death, myocardial infarction and need for revascularization in patients with left main disease or multi‐vessel CAD only [47]. In a study by Banglore et al., revascularization with Everolimus eluting stensts was compared to CABG in patients with CKD. The authors concluded that CABG was associated with higher short term risk of death, stroke and repeat revasculariza‐ tion, whereas PCI with everolimus‐eluting stent was associated with higher long‐term risk of revascularization and perhaps MI [48]. Current American College of Cardiology (ACC) and American Heart Association (AHA) guidelines recommend CABG for patients with left main

Cardiovascular Aspects of Patients with Chronic Kidney Disease and End-Stage Renal Disease

http://dx.doi.org/10.5772/intechopen.69294

109

As already mentioned CKD patients are at a higher risk of CVD. Imaging plays a central role in risk stratification and assessment of severity of CAD. A range of imaging modalities have been developed to assist with diagnosis and risk stratification of CVD in patients with CKD. Myocardial perfusion imaging (MPI) is widely used for non‐invasive assessment of myocar‐ dial ischemia due to CAD [49]. MPI can be performed using single photon emission computed tomography (SPECT) as well as positron emission tomography (PET). SPECT MPI is more widely available. It can be performed with a variety of stressors such as exercise or administra‐ tion of vasodilatory agents (adenosine or regadenoson) or dobutamine. SPECT detects areas of reduced perfusion by measuring and comparing the distribution of injected radioactive trac‐ ers such as 99 technetium or 201 thallium, when at rest and after stressor/vasodilator agents. For PET MPI stress perfusion is measured in the same way as SPECT. Various agents can be used as radiotracer including H2 15 O, ammonia or rubidium.  Although both SPECT and PET MPI have widely been studied for detection of CAD in general population, data regarding their use in CKD

Echocardiography plays a pivotal role in assessment of cardiac dysfunction in patients with or without renal insufficiency. Various cardiac abnormalities including left ventricular hyper‐ trophy (LVH), diastolic or systolic dysfunction are predictive of poor prognosis in CKD patients and can be rapidly diagnosed using 2 D trans‐thoracic echocardiogram (TTE). Stress echocardiography is an established technique used to investigate myocardial viability and ischemia. Patients can be stressed either pharmacologically with dobutamine or with exer‐ cise [50]. However, the sensitivity and specificity of stress echocardiography is modest in patients with CKD. In a systemic review by Sharma et al. sensitivity of stress echocardiogra‐ phy was 80% in patients with ESRD [51]. Factors limiting the role of stress echocardiography for detecting CAD in patients with CKD include LVH and blunted chronotropic response in

CT coronary angiography (CTA) has good sensitivity and specificity for detection of CAD in non‐ CKD population [54]. However, data is limited in patients with CKD. Iodinated contrast agent is required that increases the risk of contrast induced nephropathy. (contrast induced nephropathy

or multi‐vessel disease irrespective of renal function.

population in limited.

patients with CKD [52, 53].

**3.3. Non‐invasive cardiac imaging in patients with CKD**

Multiple studies have found that patients with CKD who undergo revascularization for CAD have worst outcomes compared to patients with normal kidney function [32, 33]. Patients with CKD have more cardiovascular risk factors at baseline [32]. Furthermore, CKD itself was independently associated with worst outcomes including increased all‐cause mortality and subsequent cardiac events [32].

In CKD revascularization procedures including percutanous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) are complicated by risk of contrast induced nephropathy (CIN) and increased risk of bleeding due to dual antiplatelet therapy. CIN is discussed in detail in separate section.

CKD results in complex hemostatic disorder manifested by increased bleeding and thrombo‐ sis. Hence the use of antiplatelet therapy has the potential for both benefit and harm. Reduced platelet aggregation, intrinsic platelet dysfunction and abnormalities in platelet‐endothelial interactions are found in CKD and may in part account for increased bleeding risk with PCI in these patients [34–36].

On the contrary, some studies have suggested the presence of pro‐thrombotic state in CKD patients that manifest by an increase in serum fibrinogen, von Willibrand factor and reduc‐ tion in antithrombin 3 [34, 37–39]. Therefore, it is unclear whether dual antiplatelet therapy after PCI is beneficial and safe in CKD patients. Furthermore, few studies have evaluated the appropriate dosing of antithrombotic agents or anticoagulants in patients with CKD [40].

Although clinical restenosis rates are not higher compared to patients with normal renal func‐ tion, on repeated angiography restenosis rates were found to be as high as 60–81% [41, 42]. Thus, absence of symptoms of restenosis in patients with chronic renal insufficiency may lead to silent ischemia and contribute to high risk of subsequent cardiac events.

CKD patients have worse outcomes after CABG. One study found in‐hospital mortality rate to be 14.6% [43]. Another study that was done on end‐stage renal disease (ESRD) patients over course of 10 years found peri‐operative mortality to be about 14% in cardiac surgery patients [44]. Even mild renal insufficiency is associated with double in‐hospitality rates in one analysis [45]. CAD is more diffuse in patients with renal dysfunction which likely contrib‐ utes higher complication rates and worst outcomes.

Szczech et al. published a study in 2001 that showed survival benefit among patients with ESRD undergoing CABG as compared to PCI, while controlling for severity of CAD, LV dysfunction and other comorbid conditions [46]. However in analysis of CREDO‐Hyoto PCI/CABG reg‐ istry Marui A et al. found CABG relative to PCI reduced risk of cardiac death, sudden death, myocardial infarction and need for revascularization in patients with left main disease or multi‐vessel CAD only [47]. In a study by Banglore et al., revascularization with Everolimus eluting stensts was compared to CABG in patients with CKD. The authors concluded that CABG was associated with higher short term risk of death, stroke and repeat revasculariza‐ tion, whereas PCI with everolimus‐eluting stent was associated with higher long‐term risk of revascularization and perhaps MI [48]. Current American College of Cardiology (ACC) and American Heart Association (AHA) guidelines recommend CABG for patients with left main or multi‐vessel disease irrespective of renal function.

## **3.3. Non‐invasive cardiac imaging in patients with CKD**

No robust evidence is yet available to ascertain whether CKD patients with chronic stable angina who undergo revascularization have a definite survival advantage compared to CKD patients on medical therapy alone. In the only randomized study of dialysis patients compar‐ ing invasive approach (PCI and coronary artery bypass graft surgery (CABG)) with medical therapy alone, the invasive approach had a clear survival benefit [31]. However medical therapy at that time only consisted of calcium channel blockers, and use of other agents proven to have survival advantage in patients with cardiovascular disease was not the norm. Furthermore, this study only included patients with diabetes mellitus. In another study done

Multiple studies have found that patients with CKD who undergo revascularization for CAD have worst outcomes compared to patients with normal kidney function [32, 33]. Patients with CKD have more cardiovascular risk factors at baseline [32]. Furthermore, CKD itself was independently associated with worst outcomes including increased all‐cause mortality and

In CKD revascularization procedures including percutanous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) are complicated by risk of contrast induced nephropathy (CIN) and increased risk of bleeding due to dual antiplatelet therapy. CIN is

CKD results in complex hemostatic disorder manifested by increased bleeding and thrombo‐ sis. Hence the use of antiplatelet therapy has the potential for both benefit and harm. Reduced platelet aggregation, intrinsic platelet dysfunction and abnormalities in platelet‐endothelial interactions are found in CKD and may in part account for increased bleeding risk with PCI

On the contrary, some studies have suggested the presence of pro‐thrombotic state in CKD patients that manifest by an increase in serum fibrinogen, von Willibrand factor and reduc‐ tion in antithrombin 3 [34, 37–39]. Therefore, it is unclear whether dual antiplatelet therapy after PCI is beneficial and safe in CKD patients. Furthermore, few studies have evaluated the appropriate dosing of antithrombotic agents or anticoagulants in patients with CKD [40].

Although clinical restenosis rates are not higher compared to patients with normal renal func‐ tion, on repeated angiography restenosis rates were found to be as high as 60–81% [41, 42]. Thus, absence of symptoms of restenosis in patients with chronic renal insufficiency may lead

CKD patients have worse outcomes after CABG. One study found in‐hospital mortality rate to be 14.6% [43]. Another study that was done on end‐stage renal disease (ESRD) patients over course of 10 years found peri‐operative mortality to be about 14% in cardiac surgery patients [44]. Even mild renal insufficiency is associated with double in‐hospitality rates in one analysis [45]. CAD is more diffuse in patients with renal dysfunction which likely contrib‐

Szczech et al. published a study in 2001 that showed survival benefit among patients with ESRD undergoing CABG as compared to PCI, while controlling for severity of CAD, LV dysfunction

to silent ischemia and contribute to high risk of subsequent cardiac events.

utes higher complication rates and worst outcomes.

in 2002, PCI did not significantly improve survival [32].

108 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

subsequent cardiac events [32].

in these patients [34–36].

discussed in detail in separate section.

As already mentioned CKD patients are at a higher risk of CVD. Imaging plays a central role in risk stratification and assessment of severity of CAD. A range of imaging modalities have been developed to assist with diagnosis and risk stratification of CVD in patients with CKD.

Myocardial perfusion imaging (MPI) is widely used for non‐invasive assessment of myocar‐ dial ischemia due to CAD [49]. MPI can be performed using single photon emission computed tomography (SPECT) as well as positron emission tomography (PET). SPECT MPI is more widely available. It can be performed with a variety of stressors such as exercise or administra‐ tion of vasodilatory agents (adenosine or regadenoson) or dobutamine. SPECT detects areas of reduced perfusion by measuring and comparing the distribution of injected radioactive trac‐ ers such as 99 technetium or 201 thallium, when at rest and after stressor/vasodilator agents.

For PET MPI stress perfusion is measured in the same way as SPECT. Various agents can be used as radiotracer including H2 15 O, ammonia or rubidium.  Although both SPECT and PET MPI have widely been studied for detection of CAD in general population, data regarding their use in CKD population in limited.

Echocardiography plays a pivotal role in assessment of cardiac dysfunction in patients with or without renal insufficiency. Various cardiac abnormalities including left ventricular hyper‐ trophy (LVH), diastolic or systolic dysfunction are predictive of poor prognosis in CKD patients and can be rapidly diagnosed using 2 D trans‐thoracic echocardiogram (TTE). Stress echocardiography is an established technique used to investigate myocardial viability and ischemia. Patients can be stressed either pharmacologically with dobutamine or with exer‐ cise [50]. However, the sensitivity and specificity of stress echocardiography is modest in patients with CKD. In a systemic review by Sharma et al. sensitivity of stress echocardiogra‐ phy was 80% in patients with ESRD [51]. Factors limiting the role of stress echocardiography for detecting CAD in patients with CKD include LVH and blunted chronotropic response in patients with CKD [52, 53].

CT coronary angiography (CTA) has good sensitivity and specificity for detection of CAD in non‐ CKD population [54]. However, data is limited in patients with CKD. Iodinated contrast agent is required that increases the risk of contrast induced nephropathy. (contrast induced nephropathy is discussed in separate section) Furthermore concerns exist that diffuse calcifications in CKD patients might render interpretation of CTA findings difficult. In patients on hemodialysis (HD) calcifications can occur in intima, where it contributes to luminal stenosis or medial where it is related to vascular stiffness. CTA might not be able to discern the difference. Despite these limi‐ tations some small studies have reported > 90% sensitivity of CTA to detect CAD in patients on HD [55]. However, coronary angiography was not used as gold standard in these studies.

and Troponin I (cTnI) are considered the preferred biochemical markers to detect myocar‐ dial injury and to diagnose acute myocardial infarction (AMI). Since the introduction of high sensitivity cardiac troponin (hs‐cTn) assays, more accurate detection of low levels of circulat‐

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111

However the increase in sensitivity of hs‐cTn for AMI is accompanied by decrease in specific‐ ity [68, 69]. In patients with chronic kidney disease elevated hs‐cTn concentrations are associ‐

The interpretation of serum markers for myocardial injury in patients with renal insufficiency remains controversial. Large scale trials of patients with acute coronary syndrome (ACS) have documented the importance of troponin elevations in risk stratification, prognosis and thera‐ peutic utilization. However most of these studies excluded patients with renal insufficiency. Cardinaels et al. recently showed that in patients with acute chest discomfort hs‐cTnT and hs‐ cTnI were strongly correlated with eGFR [70]. Although differences were small, the authors reported a greater correlation of hs‐cTnT with eGFR compared to hs‐cTnI. Furthermore, the association of hs‐cTnT is greater with eGFR as compared to any other cardiac parameters including coronary plaque severity, coronary calcium score and left ventricular structure [70]. In contrast to hs‐TnT, hs‐TnI has a greater association with LV mass compared to eGFR. Hence it is possible that hs‐TnT is more susceptible to renal clearance then hs‐cTnI. However, these

Furthermore, many investigators have hypothesized uremic‐induced skeletal myopathy may be responsible for increased troponins in patients with renal failure [66]. This conclu‐ sion is centered on the notion that uremia may promote re‐expression of cardiac TnT from injured or regenerating cardiac muscle fibers. Some anecdotal reports show elevated serum TnT levels in patients with skeletal muscle injury or inflammatory myopathies in the absence of any obvious myocardial ischemia [71, 72]. In marathon runners without any history of cor‐ onary artery disease cardiac TnT levels were elevated after running a marathon [73]. Hence cardiac troponin levels may be elevated in patients with renal insufficiency in the absence of AMI due to increased production from skeletal muscles and possible due to decreased renal clearance. It is imperative to evaluate troponin concentrations in patients with CKD in proper clinical context and utilization of other resources such as Electrocardiogram (EKG)

The heart and kidneys work together to manage blood pressure, electrolyte and fluid excre‐ tion, but most importantly extracellular fluid balance [74]. Cardio‐renal syndrome (CRS) is defined as a broad spectrum of diseases where both the heart and kidneys are involved in an

There are five types of CRSs. Type I, or acute CRS, is acute heart failure leading to acute kidney injury [74] Type II, or chronic CRS, occurs in the setting of chronic heart failure which leads to kidney injury [75]. Type III or acute nephrocardiac is caused by acute kidney injury

ing cardiac troponins became feasible [67].

differences are yet to be completely established.

to rule out AMI.

**5. Cardio‐renal Syndromes**

acute or chronic setting [75]

ated with reduced renal function.

Leading authors have advocated for combining functional imaging technique with anatomi‐ cal imaging technique for CAD screening in clinical practice. Although these hybrid tech‐ niques are potentially useful in general population, none have been validated in patients with CKD [56, 82]. Role of non‐invasive imaging for pre‐transplant evaluation of CAD is addressed in a separate section.

#### **3.4. Contrast Induced Nephropathy**

PCI in patients with CKD is challenging due to presence of complex calcified lesions and the very high risk of CIN. PCI in patients with advanced CKD is associated with increased risk of CIN which is independently associated with major adverse clinical events [57]. Outcomes are even worse if renal replacement therapy is required [57].

Pathophysiologically several mechanisms are involved in acute kidney injury caused by CIN. Studies have shown evidence of acute tubular necrosis (ATN). Two mechanism of ATN have been postulated. Direct nephrotoxicity of contrast agents has been documented [58, 59]. Furthermore, it has also been hypothesized that renal vasoconstriction, mediated by endothelin and prostaglandins resulting in medullary hypoxia causes ATN [60–62].

Studies have demonstrated a dose‐dependent relationship of acute kidney injury (AKI) caused by CIN [63]. The type of contrast alters the risk of CIN. The use of first generation hyperosmo‐ lar ionic agents is associated with a greater risk of CIN [64]. Prevention strategies for CIN that have been well established also apply to patients undergoing PCI. These include using minimal amount of contrast, avoiding ionic contrast and non‐steroidal anti‐inflammatory drugs (NSAIDs).

Most recently Galougahi et al. have described a case series of a unique approach toward revascularization in patients with CKD by sequential diagnostic angiography using ultra‐ low volumes of contrast followed by staged physiology and intravascular ultrasound (IVUS)‐ guided zero contrast PCI in three patients with severely calcified coronary lesions [65]. While such strategies have potential for more wider acceptance, at this time they are not practiced widely due to technical and procedural limitations.

## **4. Use of troponin concentration level in patients with chronic kidney disease**

Troponin proteins are present in both cardiac and skeletal muscle [66]. Cardiac troponin C is identicial to troponin C expressed in skeletal muscle. However cardiac troponin TnT and TnI are each derived from genes that are specific to the heart [66]. Hence troponin T (cTnT) and Troponin I (cTnI) are considered the preferred biochemical markers to detect myocar‐ dial injury and to diagnose acute myocardial infarction (AMI). Since the introduction of high sensitivity cardiac troponin (hs‐cTn) assays, more accurate detection of low levels of circulat‐ ing cardiac troponins became feasible [67].

However the increase in sensitivity of hs‐cTn for AMI is accompanied by decrease in specific‐ ity [68, 69]. In patients with chronic kidney disease elevated hs‐cTn concentrations are associ‐ ated with reduced renal function.

The interpretation of serum markers for myocardial injury in patients with renal insufficiency remains controversial. Large scale trials of patients with acute coronary syndrome (ACS) have documented the importance of troponin elevations in risk stratification, prognosis and thera‐ peutic utilization. However most of these studies excluded patients with renal insufficiency.

Cardinaels et al. recently showed that in patients with acute chest discomfort hs‐cTnT and hs‐ cTnI were strongly correlated with eGFR [70]. Although differences were small, the authors reported a greater correlation of hs‐cTnT with eGFR compared to hs‐cTnI. Furthermore, the association of hs‐cTnT is greater with eGFR as compared to any other cardiac parameters including coronary plaque severity, coronary calcium score and left ventricular structure [70]. In contrast to hs‐TnT, hs‐TnI has a greater association with LV mass compared to eGFR. Hence it is possible that hs‐TnT is more susceptible to renal clearance then hs‐cTnI. However, these differences are yet to be completely established.

Furthermore, many investigators have hypothesized uremic‐induced skeletal myopathy may be responsible for increased troponins in patients with renal failure [66]. This conclu‐ sion is centered on the notion that uremia may promote re‐expression of cardiac TnT from injured or regenerating cardiac muscle fibers. Some anecdotal reports show elevated serum TnT levels in patients with skeletal muscle injury or inflammatory myopathies in the absence of any obvious myocardial ischemia [71, 72]. In marathon runners without any history of cor‐ onary artery disease cardiac TnT levels were elevated after running a marathon [73]. Hence cardiac troponin levels may be elevated in patients with renal insufficiency in the absence of AMI due to increased production from skeletal muscles and possible due to decreased renal clearance. It is imperative to evaluate troponin concentrations in patients with CKD in proper clinical context and utilization of other resources such as Electrocardiogram (EKG) to rule out AMI.

## **5. Cardio‐renal Syndromes**

is discussed in separate section) Furthermore concerns exist that diffuse calcifications in CKD patients might render interpretation of CTA findings difficult. In patients on hemodialysis (HD) calcifications can occur in intima, where it contributes to luminal stenosis or medial where it is related to vascular stiffness. CTA might not be able to discern the difference. Despite these limi‐ tations some small studies have reported > 90% sensitivity of CTA to detect CAD in patients on HD [55]. However, coronary angiography was not used as gold standard in these studies.

Leading authors have advocated for combining functional imaging technique with anatomi‐ cal imaging technique for CAD screening in clinical practice. Although these hybrid tech‐ niques are potentially useful in general population, none have been validated in patients with CKD [56, 82]. Role of non‐invasive imaging for pre‐transplant evaluation of CAD is addressed

PCI in patients with CKD is challenging due to presence of complex calcified lesions and the very high risk of CIN. PCI in patients with advanced CKD is associated with increased risk of CIN which is independently associated with major adverse clinical events [57]. Outcomes are

Pathophysiologically several mechanisms are involved in acute kidney injury caused by CIN. Studies have shown evidence of acute tubular necrosis (ATN). Two mechanism of ATN have been postulated. Direct nephrotoxicity of contrast agents has been documented [58, 59]. Furthermore, it has also been hypothesized that renal vasoconstriction, mediated by endothelin

Studies have demonstrated a dose‐dependent relationship of acute kidney injury (AKI) caused by CIN [63]. The type of contrast alters the risk of CIN. The use of first generation hyperosmo‐ lar ionic agents is associated with a greater risk of CIN [64]. Prevention strategies for CIN that have been well established also apply to patients undergoing PCI. These include using minimal amount of contrast, avoiding ionic contrast and non‐steroidal anti‐inflammatory drugs (NSAIDs). Most recently Galougahi et al. have described a case series of a unique approach toward revascularization in patients with CKD by sequential diagnostic angiography using ultra‐ low volumes of contrast followed by staged physiology and intravascular ultrasound (IVUS)‐ guided zero contrast PCI in three patients with severely calcified coronary lesions [65]. While such strategies have potential for more wider acceptance, at this time they are not practiced

**4. Use of troponin concentration level in patients with chronic kidney**

Troponin proteins are present in both cardiac and skeletal muscle [66]. Cardiac troponin C is identicial to troponin C expressed in skeletal muscle. However cardiac troponin TnT and TnI are each derived from genes that are specific to the heart [66]. Hence troponin T (cTnT)

in a separate section.

**disease**

**3.4. Contrast Induced Nephropathy**

even worse if renal replacement therapy is required [57].

110 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

widely due to technical and procedural limitations.

and prostaglandins resulting in medullary hypoxia causes ATN [60–62].

The heart and kidneys work together to manage blood pressure, electrolyte and fluid excre‐ tion, but most importantly extracellular fluid balance [74]. Cardio‐renal syndrome (CRS) is defined as a broad spectrum of diseases where both the heart and kidneys are involved in an acute or chronic setting [75]

There are five types of CRSs. Type I, or acute CRS, is acute heart failure leading to acute kidney injury [74] Type II, or chronic CRS, occurs in the setting of chronic heart failure which leads to kidney injury [75]. Type III or acute nephrocardiac is caused by acute kidney injury

**Table 1.** Classification of cardio‐renal syndromes.

leading to acute heart failure, example Uremic cardiomyopathy [75]. Type IV, or chronic nephrocardiac, occurs with chronic kidney disease which causes heart failure for example diastolic heart failure and kidney failure [75]. Lastly, is type V which is secondary to systemic disease leading to heart and kidney failure [75]. **Table 1** summarizes the five types of CRSs.

Management of patients with acute decompensated heart failure and worsening renal func‐ tion can be challenging. A randomized control trial compared the effect of venovenous ultra‐ filtration with intravenous diuretics on renal function with acute decompensated heart failure and worsening renal function [76]. This study found that there was no significant difference between diuretics and ultrafiltration in weight loss, mortality or the rate of re‐hospitalization for acute decompensated heart failure during a 60 day follow‐up.

## **6. CAD evaluation before kidney transplant**

Cardiovascular disease is the leading cause of morbidity and mortality in patients with end‐stage renal disease (ESRD) and in those after kidney transplant [77, 78]. Based on Medicare billing claims incidence of myocardial infarction have ranged from 8.7 to 16.7% by 3 years after kidney transplant listing and from 4.7 to 11.1% after kidney transplanta‐ tion [79]. Cardiovascular disease accounts for 30% of the overall mortality especially in the peri‐transplantation period [80]. So, the preoperative cardiovascular risk assessment is of high importance before the kidney transplant surgery as these patients are closely followed up for over the 3 years and events are reported to the United Network for Organ Sharing (UNOS).

**Figure 1** summarizes a clinical approach to preoperative cardiovascular risk assessment before kidney transplantation.

**Figure 1.** Pre‐operative cardiovascular risk assessment before kidney transplant.

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Cardiovascular Aspects of Patients with Chronic Kidney Disease and End-Stage Renal Disease http://dx.doi.org/10.5772/intechopen.69294 113

**Figure 1.** Pre‐operative cardiovascular risk assessment before kidney transplant.

leading to acute heart failure, example Uremic cardiomyopathy [75]. Type IV, or chronic nephrocardiac, occurs with chronic kidney disease which causes heart failure for example diastolic heart failure and kidney failure [75]. Lastly, is type V which is secondary to systemic disease leading to heart and kidney failure [75]. **Table 1** summarizes the five types of CRSs. Management of patients with acute decompensated heart failure and worsening renal func‐ tion can be challenging. A randomized control trial compared the effect of venovenous ultra‐ filtration with intravenous diuretics on renal function with acute decompensated heart failure and worsening renal function [76]. This study found that there was no significant difference between diuretics and ultrafiltration in weight loss, mortality or the rate of re‐hospitalization

**Cardiorenal type Inciting event Secondary event Example**

Type III Acute kidney injury Acute cardiac disease (heart

112 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Type IV Chronic kidney disease Decreased cardiac output,

Type V Systemic disease Both kidney and heart

**Table 1.** Classification of cardio‐renal syndromes.

Type I Acute heart failure Acute kidney injury Acute coronary syndrome

edema)

Type II Chronic heart failure Progressive kidney disease Chronic heart failure leading to

failure, arrhythmia, pulmonary

Increased blood pressure leading

to cardiac hypertrophy

dysfunction and disease

leading to decreased cardiac output and acute kidney injury

decreased cardiac output

Acute kidney failure (drug induced, glomerulonephritis)

Chronic kidney disease due to chronic hypertension or diabetic nephropathy

diabetes mellitus, sepsis, lupus

Cardiovascular disease is the leading cause of morbidity and mortality in patients with end‐stage renal disease (ESRD) and in those after kidney transplant [77, 78]. Based on Medicare billing claims incidence of myocardial infarction have ranged from 8.7 to 16.7% by 3 years after kidney transplant listing and from 4.7 to 11.1% after kidney transplanta‐ tion [79]. Cardiovascular disease accounts for 30% of the overall mortality especially in the peri‐transplantation period [80]. So, the preoperative cardiovascular risk assessment is of high importance before the kidney transplant surgery as these patients are closely followed up for over the 3 years and events are reported to the United Network for Organ

**Figure 1** summarizes a clinical approach to preoperative cardiovascular risk assessment

for acute decompensated heart failure during a 60 day follow‐up.

**6. CAD evaluation before kidney transplant**

Sharing (UNOS).

before kidney transplantation.

## *Step 1: Assess for presence of active cardiac condition:*

Patients with active cardiac condition should be ruled out by detailed history and physical examination. Active cardiac conditions include‐ unstable coronary syndromes (e.g., unstable angina, severe angina, or recent MI), decompensated heart failure, significant arrhythmias, and severe valvular disease. The presence of one or more of these conditions is associated with high rates of perioperative cardiovascular morbidity and mortality and may require delay or cancellation of surgery.

*Step 5: Revascularization*

functional grafts.

cular diseases.

cardiovascular event [86].

**7.2. Left ventricle hypertrophy**

of stable ischemic heart disease.

risk factors will be discussed.

**7.1. Non‐traditional risk factors**

**7. Cardiovascular risk in renal transplant patients**

Revascularization is done either with PCI with stent or CABG after assessment of extent of obstructive CAD and risk factors like diabetes as per the ACC/AHA guidelines for management

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115

Renal transplant (RT) has dramatically improved the survival and quality of life for success‐ ful recipients. Despite advancements in surgical methods and medical management of RT patients, cardiovascular disease (CVD) remains the leading cause of death in patients with

The risk of CVD improves after RT when compared to patients with end‐stage renal disease (ESRD) awaiting transplantation. However, mortality due to CVD is ten times higher in renal

The increased risk of CVD cannot be explained by traditional risk factors alone.Non‐tradi‐

Traditional CVD risk factors include Hypertension, Diabetes Mellitus, Dyslipidemia, Tobacco use, and Obesity. In this section the effect of immunosuppressive agents on these traditional

In addition to traditional CVD risk factors, RT patients develop specific risk factors related to ESRD including but not limited to endothelial dysfunction, electrolyte imbalances (calcium

A retrospective study using database from Données Informatisées et Validées en Transplantation (DIVAT) evaluated 244 RT patients post‐transplant for 1 year for ST‐segment elevation myocardial infarction (STEMI), non‐ST‐segment elevation myocardial infarction (NSTEMI), new onset atrial fibrillation or ventricular fibrillation, and death from cardiovas‐

The results revealed that a past medical history of cardiovascular disease (Hazard Ratio (HR) = 2.06, p = 0.03), left ventricular hypertrophy (HR = 2.04, p = 0.04) and abnormal myo‐ cardial perfusion imaging (HR = 2.18, p = 0.05) were associated with a higher risk of early

LVH is a common co‐morbidity observed in chronic kidney disease (CKD) and end‐stage renal disease (ESRD) patients [87]. Multiple factors have been implicated as the cause of LVH

and phosphorous), anemia and variations in the plasma volume following dialysis.

transplant recipients than the age and sex‐matched general population [83, 84].

tional risk factors in RT patient population also play a pivotal role [85].

#### *Step 2: Assess for presence of risk factors*

After excluding active cardiac condition, presence of risk factors for CAD should be assessed. Traditional Framingham risk score has modest to moderate ability to predict long‐term coronary events among kidney transplantation patients. Risk stratification based on 2007 Lisbon conference [81] strategy improved the sensitivity and specificity for the identifica‐ tion of CAD (sensitivity, 94% vs. 77%; specificity, 33% vs. 24%) when compared to ACC/ AHA recommended CAD risk stratification strategy The risk factors for CAD Aeemed rel‐ evant to transplantation candidates in the Lisbon Conference report include diabetes mellitus, prior cardiovascular disease, >1 year on dialysis, left ventricular hypertrophy, age > 60 years, smoking, hypertension, and dyslipidemia.

Currently, the preoperative assessment is done based on the ACC/AHA scientific statement [78]. As per this "Noninvasive stress testing may be considered in kidney transplantation candidates with no active cardiac conditions based on the presence of multiple coronary artery disease (CAD) risk factors regardless of functional status. Relevant risk factors among transplantation candidates include diabetes mellitus, prior cardiovascular disease, more than 1 year on dialysis, left ventricular hypertrophy, age greater than 60 years, smoking, hyperten‐ sion, and dyslipidemia. The specific number of risk factors that should be used to prompt testing remains to be determined, but the committee considers 3 or more as reasonable (Class IIb; Level of Evidence C)."

#### *Step 3: Non‐invasive testing*

Most common non‐invasive stress testing modalities include dobutamine stress echocar‐ diogram (DSE) and MPI. The diagnostic accuracy of these tests varies with sensitivity rang‐ ing from 0.29 to 0.92 (MPI) 0.44–0.89 (DSE) and specificity of around 0.67–0.89 (MPI) and 0.71–0.94 (DSE) [78]. MPI accuracy can be effected by presence of balanced ischemia result‐ ing in more false negative results. Recently, coronary computed tomography angiography (CCTA) was shown to be a reliable test with high sensitivity (93%) and a high negative pre‐ dictive value (97%) for diagnosing obstructive CAD before kidney transplantation. Hybrid imaging techniques like combining CCTA and SPECT have a sensitivity and specificity of 67 and 86% [82]

#### *Step 4: Coronary angiography*

Based on the noninvasive testing, coronary angiography is performed as needed to determine the presence and extent of obstructive CAD.

#### *Step 5: Revascularization*

*Step 1: Assess for presence of active cardiac condition:*

114 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

delay or cancellation of surgery.

*Step 2: Assess for presence of risk factors*

smoking, hypertension, and dyslipidemia.

IIb; Level of Evidence C)." *Step 3: Non‐invasive testing*

67 and 86% [82]

*Step 4: Coronary angiography*

the presence and extent of obstructive CAD.

Patients with active cardiac condition should be ruled out by detailed history and physical examination. Active cardiac conditions include‐ unstable coronary syndromes (e.g., unstable angina, severe angina, or recent MI), decompensated heart failure, significant arrhythmias, and severe valvular disease. The presence of one or more of these conditions is associated with high rates of perioperative cardiovascular morbidity and mortality and may require

After excluding active cardiac condition, presence of risk factors for CAD should be assessed. Traditional Framingham risk score has modest to moderate ability to predict long‐term coronary events among kidney transplantation patients. Risk stratification based on 2007 Lisbon conference [81] strategy improved the sensitivity and specificity for the identifica‐ tion of CAD (sensitivity, 94% vs. 77%; specificity, 33% vs. 24%) when compared to ACC/ AHA recommended CAD risk stratification strategy The risk factors for CAD Aeemed rel‐ evant to transplantation candidates in the Lisbon Conference report include diabetes mellitus, prior cardiovascular disease, >1 year on dialysis, left ventricular hypertrophy, age > 60 years,

Currently, the preoperative assessment is done based on the ACC/AHA scientific statement [78]. As per this "Noninvasive stress testing may be considered in kidney transplantation candidates with no active cardiac conditions based on the presence of multiple coronary artery disease (CAD) risk factors regardless of functional status. Relevant risk factors among transplantation candidates include diabetes mellitus, prior cardiovascular disease, more than 1 year on dialysis, left ventricular hypertrophy, age greater than 60 years, smoking, hyperten‐ sion, and dyslipidemia. The specific number of risk factors that should be used to prompt testing remains to be determined, but the committee considers 3 or more as reasonable (Class

Most common non‐invasive stress testing modalities include dobutamine stress echocar‐ diogram (DSE) and MPI. The diagnostic accuracy of these tests varies with sensitivity rang‐ ing from 0.29 to 0.92 (MPI) 0.44–0.89 (DSE) and specificity of around 0.67–0.89 (MPI) and 0.71–0.94 (DSE) [78]. MPI accuracy can be effected by presence of balanced ischemia result‐ ing in more false negative results. Recently, coronary computed tomography angiography (CCTA) was shown to be a reliable test with high sensitivity (93%) and a high negative pre‐ dictive value (97%) for diagnosing obstructive CAD before kidney transplantation. Hybrid imaging techniques like combining CCTA and SPECT have a sensitivity and specificity of

Based on the noninvasive testing, coronary angiography is performed as needed to determine

Revascularization is done either with PCI with stent or CABG after assessment of extent of obstructive CAD and risk factors like diabetes as per the ACC/AHA guidelines for management of stable ischemic heart disease.

## **7. Cardiovascular risk in renal transplant patients**

Renal transplant (RT) has dramatically improved the survival and quality of life for success‐ ful recipients. Despite advancements in surgical methods and medical management of RT patients, cardiovascular disease (CVD) remains the leading cause of death in patients with functional grafts.

The risk of CVD improves after RT when compared to patients with end‐stage renal disease (ESRD) awaiting transplantation. However, mortality due to CVD is ten times higher in renal transplant recipients than the age and sex‐matched general population [83, 84].

The increased risk of CVD cannot be explained by traditional risk factors alone.Non‐tradi‐ tional risk factors in RT patient population also play a pivotal role [85].

Traditional CVD risk factors include Hypertension, Diabetes Mellitus, Dyslipidemia, Tobacco use, and Obesity. In this section the effect of immunosuppressive agents on these traditional risk factors will be discussed.

## **7.1. Non‐traditional risk factors**

In addition to traditional CVD risk factors, RT patients develop specific risk factors related to ESRD including but not limited to endothelial dysfunction, electrolyte imbalances (calcium and phosphorous), anemia and variations in the plasma volume following dialysis.

A retrospective study using database from Données Informatisées et Validées en Transplantation (DIVAT) evaluated 244 RT patients post‐transplant for 1 year for ST‐segment elevation myocardial infarction (STEMI), non‐ST‐segment elevation myocardial infarction (NSTEMI), new onset atrial fibrillation or ventricular fibrillation, and death from cardiovas‐ cular diseases.

The results revealed that a past medical history of cardiovascular disease (Hazard Ratio (HR) = 2.06, p = 0.03), left ventricular hypertrophy (HR = 2.04, p = 0.04) and abnormal myo‐ cardial perfusion imaging (HR = 2.18, p = 0.05) were associated with a higher risk of early cardiovascular event [86].

## **7.2. Left ventricle hypertrophy**

LVH is a common co‐morbidity observed in chronic kidney disease (CKD) and end‐stage renal disease (ESRD) patients [87]. Multiple factors have been implicated as the cause of LVH including over‐activation of the sympathetic nervous system, volume overload, hypertension, inhibition of nitric oxide, arterial stiffness, diabetes, dyslipidemia, endothelial dysfunction, and anemia of chronic disease. Electrocardiographic (ECG) evidence of LVH in the first year after RT was found to be an independent risk factor for death and subsequent congestive heart failure [88]. Persistent or de novo LVH is also a strong independent risk factor for death after 5 years, confirming the continuing importance of LVH even in the late post‐transplant period [88].

survival and increased risk of cardiovascular events [91]. These findings were similar to CKD

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117

According to the follow‐up data from the ALERT study, anemia is a predictor of graft loss but not associated with an increased incidence of cardiovascular morbidity and mortality or

No immunosuppressive drug has been directly associated with cardiovascular events. However, immunosuppressive drugs impact the traditional risk factors and play a crucial role.

According to the historical literature, corticosteroids were believed to cause elevated blood pressure by water and salt retention via an effect on the mineralocorticoid receptor. However, recent data points that blockade of NO formation by inhibition of both inducible and endo‐ thelial nitric oxide synthase (eNOS), inhibition of transmembrane arginine transport and

Anti‐proliferative agents were thought to worsen hypertension in RT patients. However recent studies in patients with systemic lupus erythematosus suggests an improved blood

Cyclosporine monotherapy induces hypertension to the same extent as corticosteroids [94]. The mechanism by which cyclosporine and tacrolimus increase blood pressure is complex. One proposed mechanism is that cyclosporine stimulates transmembrane influxes of calcium, thereby leading to vascular smooth muscle cell contraction and vasoconstriction.

inhibition of the synthesis of the NOS cofactor BH4 play a prominent role [93].

pressure control with the use of mycophenolate mofetil.

RT patients are usually on a combination of following maintenance medications:

*Antiproliferative agents: Mycophenolate Mofetil and Azathioprine.*

*Calcineurin inhibitors: Tacrolimus and Cyclosporine.*

*mTOR inhibitors: Sirolimus and Everolimus.*

patients without transplant as previously described.

all‐cause mortality in RT patients [92].

**7.7. Immunosuppressive therapy**

*Corticosteroids: Prednisone.*

**8. Hypertension**

**8.1. Corticosteroids**

**8.2. Antiproliferative agents**

**8.3. Calcineurin inhibitors**

**7.6. Anemia**

The presence of LVH is a important prognostic factor for CVD mortality and morbidity in RT patients. Whether a successful renal transplantation can reverse LVH still remains a debatable issue [87].

## **7.3. Over‐activation of the sympathetic nervous system**

To entertain the hypothesis that development of LVH may be connected to excessive activa‐ tion of the sympathetic nervous system, the effect of pre‐transplant bilateral native nephrec‐ tomy on left ventricular mass and function has been evaluated. A study group of 32 patients who had undergone pre‐transplant bilateral native nephrectomy were compared to 32 control group patients and evaluated with echocardiography and/or cardiac magnetic resonance (CMR) [89].

After a 90‐month follow‐up, bilateral native nephrectomy before transplantation was associ‐ ated with a lower left ventricular mass index (LVMI; p = 0.001), left atrial volume index (LAVI; p = 0.004), and a lower grade (grade I) of left ventricular diastolic dysfunction [89]. In compar‐ ison with controls, the study group had lower systolic blood pressure (p = 0.04) and required a fewer number of anti‐hypertensive medications (p = 0.001) [89].

## **7.4. Inflammatory state**

Pro‐inflammatory markers have also been studied in RT patient population. Neopterin is syn‐ thesized by macrophages upon stimulation by interferon‐gamma. Serum neopterin is a marker of a pro‐inflammatory state in RT patients. Clinical trial data has revealed that Neopterin is associated with cardiovascular events and all‐cause mortality in renal transplant patients.

The Assessment of LEscol in Renal Transplant (ALERT) trial prospectively analyzed RT patients with stable graft for an association between serum neopterin and subsequent clinical events: graft loss, major cardiovascular events (MACE) and all‐cause mortality.The long‐term follow‐up suggests that neopterin‐to‐creatinine ratio is significantly associated with MACE (p = 0.009) and all‐cause mortality (p = 0.002) [90].

## **7.5. Proteinuria**

A prospective trial of 90 RT patients with normal graft function in the post‐transplantation period (3–5 years) investigated the association between proteinuria and graft/patient survival and to determine whether proteinuria may be a predictor for cardiovascular disease. High‐ grade (≥500 mg/24 hours) proteinuria in RT patients is strongly associated with poor graft survival and increased risk of cardiovascular events [91]. These findings were similar to CKD patients without transplant as previously described.

#### **7.6. Anemia**

including over‐activation of the sympathetic nervous system, volume overload, hypertension, inhibition of nitric oxide, arterial stiffness, diabetes, dyslipidemia, endothelial dysfunction, and anemia of chronic disease. Electrocardiographic (ECG) evidence of LVH in the first year after RT was found to be an independent risk factor for death and subsequent congestive heart failure [88]. Persistent or de novo LVH is also a strong independent risk factor for death after 5 years, confirming the continuing importance of LVH even in the late post‐transplant

The presence of LVH is a important prognostic factor for CVD mortality and morbidity in RT patients. Whether a successful renal transplantation can reverse LVH still remains a debatable

To entertain the hypothesis that development of LVH may be connected to excessive activa‐ tion of the sympathetic nervous system, the effect of pre‐transplant bilateral native nephrec‐ tomy on left ventricular mass and function has been evaluated. A study group of 32 patients who had undergone pre‐transplant bilateral native nephrectomy were compared to 32 control group patients and evaluated with echocardiography and/or cardiac magnetic resonance

After a 90‐month follow‐up, bilateral native nephrectomy before transplantation was associ‐ ated with a lower left ventricular mass index (LVMI; p = 0.001), left atrial volume index (LAVI; p = 0.004), and a lower grade (grade I) of left ventricular diastolic dysfunction [89]. In compar‐ ison with controls, the study group had lower systolic blood pressure (p = 0.04) and required

Pro‐inflammatory markers have also been studied in RT patient population. Neopterin is syn‐ thesized by macrophages upon stimulation by interferon‐gamma. Serum neopterin is a marker of a pro‐inflammatory state in RT patients. Clinical trial data has revealed that Neopterin is associated with cardiovascular events and all‐cause mortality in renal transplant patients.

The Assessment of LEscol in Renal Transplant (ALERT) trial prospectively analyzed RT patients with stable graft for an association between serum neopterin and subsequent clinical events: graft loss, major cardiovascular events (MACE) and all‐cause mortality.The long‐term follow‐up suggests that neopterin‐to‐creatinine ratio is significantly associated with MACE

A prospective trial of 90 RT patients with normal graft function in the post‐transplantation period (3–5 years) investigated the association between proteinuria and graft/patient survival and to determine whether proteinuria may be a predictor for cardiovascular disease. High‐ grade (≥500 mg/24 hours) proteinuria in RT patients is strongly associated with poor graft

**7.3. Over‐activation of the sympathetic nervous system**

116 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

a fewer number of anti‐hypertensive medications (p = 0.001) [89].

(p = 0.009) and all‐cause mortality (p = 0.002) [90].

period [88].

issue [87].

(CMR) [89].

**7.4. Inflammatory state**

**7.5. Proteinuria**

According to the follow‐up data from the ALERT study, anemia is a predictor of graft loss but not associated with an increased incidence of cardiovascular morbidity and mortality or all‐cause mortality in RT patients [92].

## **7.7. Immunosuppressive therapy**

RT patients are usually on a combination of following maintenance medications:

*Corticosteroids: Prednisone.*

*Antiproliferative agents: Mycophenolate Mofetil and Azathioprine.*

*Calcineurin inhibitors: Tacrolimus and Cyclosporine.*

*mTOR inhibitors: Sirolimus and Everolimus.*

No immunosuppressive drug has been directly associated with cardiovascular events. However, immunosuppressive drugs impact the traditional risk factors and play a crucial role.

## **8. Hypertension**

#### **8.1. Corticosteroids**

According to the historical literature, corticosteroids were believed to cause elevated blood pressure by water and salt retention via an effect on the mineralocorticoid receptor. However, recent data points that blockade of NO formation by inhibition of both inducible and endo‐ thelial nitric oxide synthase (eNOS), inhibition of transmembrane arginine transport and inhibition of the synthesis of the NOS cofactor BH4 play a prominent role [93].

#### **8.2. Antiproliferative agents**

Anti‐proliferative agents were thought to worsen hypertension in RT patients. However recent studies in patients with systemic lupus erythematosus suggests an improved blood pressure control with the use of mycophenolate mofetil.

#### **8.3. Calcineurin inhibitors**

Cyclosporine monotherapy induces hypertension to the same extent as corticosteroids [94]. The mechanism by which cyclosporine and tacrolimus increase blood pressure is complex. One proposed mechanism is that cyclosporine stimulates transmembrane influxes of calcium, thereby leading to vascular smooth muscle cell contraction and vasoconstriction. Other proposed mechanisms include increased production of endothelin 1 (ET‐1), transform‐ ing growth factor (TGF), renin, and inhibition of NO production by multiple pathways.

and impaired glucose tolerance. Additionally, transplant related risk factors also play a role: immunosuppressive medications, HLA mismatch, donor gender, type of underlying renal

Cardiovascular Aspects of Patients with Chronic Kidney Disease and End-Stage Renal Disease

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119

The implications of PTDM in patient outcomes are not well established, but data from the USRDS/UNOS have shown that PTDM increases the risk of post‐transplant myocardial

Corticosteroids lead to development of PTDM by enhancing insulin resistance. PTDM is

There is no data suggesting that mycophenolate mofetil or azathioprine play a role in devel‐

RT patients receiving calcineurin inhibitors have a higher incidence of PTDM. The etiology is impairment in pancreatic beta‐cell secretory function [104]. Dose reduction has been shown to reverse diabetes in majority of the affected patients. The incidence of PTDM with tacrolimus is postulated to be as high as 20%. The higher incidence of PTDM with tacrolimus versus cyclosporine is believed to be due to stronger potency of tacrolimus in calcineurin inhibition

Tacrolimus leads to PTDM in a dose‐dependent manner. It leads to complete reversible inhi‐ bition of the insulin gene transcription with no acute effects on insulin secretion or the glucose uptake by insulin. Therefore, in majority of patients, PTDM is reversible after reducing the

There is no data suggesting that sirolimus or everolimus plays a role in development of PTDM.

Corticosteroids negatively impact blood pressure, lipid profile, and glucose metabolism. Randomized trials have shown that corticosteroid withdrawal or corticosteroid‐free immu‐

nosuppression improves hypertension, dyslipidemia, and glucose metabolism [106].

**11. Management of immunosuppressive agents in controlling**

disease and viral infections (HCV and CMV) [102].

reversible by cessation of corticosteroids.

dose of tacrolimus and withdrawing corticosteroids.

**10.2. Antiproliferative agents**

**10.3. Calcineurin inhibitors**

than cyclosporine [105].

**10.4. mTOR inhibitors**

**risk factors**

**11.1. Corticosteroids**

infarction [103].

**10.1. Corticosteroids**

opment of PTDM.

Recent data suggests that tacrolimus results in less renal vasoconstriction than cyclosporine. RT patients being treated with tacrolimus and equivalent dosages of corticosteroids require fewer anti‐hypertensive medications than patients being treated with cyclosporine [95].

## **9. Dyslipidemia**

#### **9.1. Corticosteroids**

Corticosteroids increase total cholesterol, low‐density lipoprotein (LDL), high‐ density lipo‐ protein (HDL), and hepatic synthesis of very low‐density lipoprotein (VLDL) [96]. Corti‐ costeroids lead to decreased LDL receptor synthesis and subsequent expression, thereby leading to reduced uptake and degradation of LDL [97].

## **9.2. Calcineurin inhibitors**

Cyclosporine increases total cholesterol, LDL, and VLDL but decreases HDL. Cyclosporine decreases the activity of lipoprotein lipase (LPL) leading to hypertriglyceridemia. It also impairs the clearance of LDL by a similar mechanism to corticosteroids [98].

When comparing patients on tacrolimus versus cyclosporine, tacrolimus‐treated patients have lower total cholesterol, LDL, and triglycerides. The levels of HDL are comparable. In a randomized, prospective trial evaluating RT patients with conversion from cyclosporine to tacrolimus, total cholesterol improved significantly by a mean of 0.5 mmol/L, LDL by 0.35 mmol/L and triglycerides by 0.4 mmol/L. These results were sustained up to 2 years after conversion [99].

#### **9.3. mTOR inhibitors**

Sirolimus is notorious for causing hyperlipidemia; increasing VLDL and LDL. One hypothesis is that sirolimus increases hepatic production of triglycerides and secretion of VLDL [100]. In clini‐ cal trials evaluating serum lipid profile, the addition of sirolimus 10 milligrams to cyclosporine and corticosteroids for 6 weeks increased both total cholesterol and LDL by 50% and triglycer‐ ides by almost 100%. The effects were fully reversible after discontinuation of sirolimus [100].

## **10. Diabetes mellitus**

Post‐transplantation diabetes mellitus (PTDM) has evolved into a concerning challenge in RT patients. Approximately one‐third of nondiabetic kidney transplant recipients develop persistent impaired glucose metabolism by 6 months post‐transplantation [101]. Risk factors for PTDM include age, obesity, African American race and Hispanic ethnicity, family history and impaired glucose tolerance. Additionally, transplant related risk factors also play a role: immunosuppressive medications, HLA mismatch, donor gender, type of underlying renal disease and viral infections (HCV and CMV) [102].

The implications of PTDM in patient outcomes are not well established, but data from the USRDS/UNOS have shown that PTDM increases the risk of post‐transplant myocardial infarction [103].

## **10.1. Corticosteroids**

Other proposed mechanisms include increased production of endothelin 1 (ET‐1), transform‐ ing growth factor (TGF), renin, and inhibition of NO production by multiple pathways.

Recent data suggests that tacrolimus results in less renal vasoconstriction than cyclosporine. RT patients being treated with tacrolimus and equivalent dosages of corticosteroids require fewer anti‐hypertensive medications than patients being treated with cyclosporine [95].

Corticosteroids increase total cholesterol, low‐density lipoprotein (LDL), high‐ density lipo‐ protein (HDL), and hepatic synthesis of very low‐density lipoprotein (VLDL) [96]. Corti‐ costeroids lead to decreased LDL receptor synthesis and subsequent expression, thereby

Cyclosporine increases total cholesterol, LDL, and VLDL but decreases HDL. Cyclosporine decreases the activity of lipoprotein lipase (LPL) leading to hypertriglyceridemia. It also

When comparing patients on tacrolimus versus cyclosporine, tacrolimus‐treated patients have lower total cholesterol, LDL, and triglycerides. The levels of HDL are comparable. In a randomized, prospective trial evaluating RT patients with conversion from cyclosporine to tacrolimus, total cholesterol improved significantly by a mean of 0.5 mmol/L, LDL by 0.35 mmol/L and triglycerides by 0.4 mmol/L. These results were sustained up to 2 years after

Sirolimus is notorious for causing hyperlipidemia; increasing VLDL and LDL. One hypothesis is that sirolimus increases hepatic production of triglycerides and secretion of VLDL [100]. In clini‐ cal trials evaluating serum lipid profile, the addition of sirolimus 10 milligrams to cyclosporine and corticosteroids for 6 weeks increased both total cholesterol and LDL by 50% and triglycer‐ ides by almost 100%. The effects were fully reversible after discontinuation of sirolimus [100].

Post‐transplantation diabetes mellitus (PTDM) has evolved into a concerning challenge in RT patients. Approximately one‐third of nondiabetic kidney transplant recipients develop persistent impaired glucose metabolism by 6 months post‐transplantation [101]. Risk factors for PTDM include age, obesity, African American race and Hispanic ethnicity, family history

impairs the clearance of LDL by a similar mechanism to corticosteroids [98].

leading to reduced uptake and degradation of LDL [97].

118 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**9. Dyslipidemia**

**9.1. Corticosteroids**

**9.2. Calcineurin inhibitors**

conversion [99].

**9.3. mTOR inhibitors**

**10. Diabetes mellitus**

Corticosteroids lead to development of PTDM by enhancing insulin resistance. PTDM is reversible by cessation of corticosteroids.

#### **10.2. Antiproliferative agents**

There is no data suggesting that mycophenolate mofetil or azathioprine play a role in devel‐ opment of PTDM.

## **10.3. Calcineurin inhibitors**

RT patients receiving calcineurin inhibitors have a higher incidence of PTDM. The etiology is impairment in pancreatic beta‐cell secretory function [104]. Dose reduction has been shown to reverse diabetes in majority of the affected patients. The incidence of PTDM with tacrolimus is postulated to be as high as 20%. The higher incidence of PTDM with tacrolimus versus cyclosporine is believed to be due to stronger potency of tacrolimus in calcineurin inhibition than cyclosporine [105].

Tacrolimus leads to PTDM in a dose‐dependent manner. It leads to complete reversible inhi‐ bition of the insulin gene transcription with no acute effects on insulin secretion or the glucose uptake by insulin. Therefore, in majority of patients, PTDM is reversible after reducing the dose of tacrolimus and withdrawing corticosteroids.

#### **10.4. mTOR inhibitors**

There is no data suggesting that sirolimus or everolimus plays a role in development of PTDM.

## **11. Management of immunosuppressive agents in controlling risk factors**

#### **11.1. Corticosteroids**

Corticosteroids negatively impact blood pressure, lipid profile, and glucose metabolism. Randomized trials have shown that corticosteroid withdrawal or corticosteroid‐free immu‐ nosuppression improves hypertension, dyslipidemia, and glucose metabolism [106].

## **11.2. Calcineurin inhibitors**

In patients receiving cyclosporine combined with mycophenolate mofetil, a 50% reduction in cyclosporine dose or complete cyclosporine withdrawal from a mycophenolate mofetil or sirolimus‐based regimen results in fewer anti‐hypertensive medications [106]. Tacrolimus increases the risk of PTDM more than cyclosporine, therefore, switching from tacrolimus to cyclosporine may lead to improvement in PTDM.

**References**

Kidney International. 2007;**72**(3):247‐259

2006;**17**(8):2275‐2284

2007;**298**(17):2038‐2047

2003;**41**(1):47‐55

2003;**41**(8):1364‐1372

Cardiology. 2004;**13**(2):81‐90

2005;**365**(9456):331‐340

Nephrology. 2007;**18**(4):1307‐1315

tive meta‐analysis. Lancet. 2010;**375**(9731):2073‐2081

data. The Lancet Diabetes & Endocrinology. 2015;**3**(7):514‐525

[1] Levey AS. et al. Chronic kidney disease as a global public health problem: Approaches and initiatives–A position statement from kidney disease improving global outcomes.

Cardiovascular Aspects of Patients with Chronic Kidney Disease and End-Stage Renal Disease

http://dx.doi.org/10.5772/intechopen.69294

121

[2] Wen CP. et al. All‐cause mortality attributable to chronic kidney disease: A prospective cohort study based on 462 293 adults in Taiwan. Lancet. 2008;**371**(9631):2173‐2182

[3] Chadban SJ. et al. Prevalence of kidney damage in Australian adults: The AusDiab kid‐ ney study. Journal of the American Society of Nephrology. 2003;**14**(7 Suppl 2):S131‐S138

[4] Hallan SI. et al. International comparison of the relationship of chronic kidney dis‐ ease prevalence and ESRD risk. Journal of the American Society of Nephrology.

[5] Coresh J. et al. Prevalence of chronic kidney disease in the United States. Jama.

[6] Imran S. et al. Burden of chronic kidney disease in an urban city of Pakistan, a cross‐sec‐

[7] Manjunath G. et al. Level of kidney function as a risk factor for atherosclerotic cardio‐ vascular outcomes in the community. Journal of the American College of Cardiology.

[8] Fried LF. et al. Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. Journal of the American College of Cardiology.

[9] Shlipak MG. et al. Chronic renal insufficiency and cardiovascular events in the elderly: Findings from the Cardiovascular Health Study. The American Journal of Geriatric

[10] Kottgen A. et al. Reduced kidney function as a risk factor for incident heart failure: The atherosclerosis risk in communities (ARIC) study. Journal of the American Society of

[11] Matsushita K. et al. Association of estimated glomerular filtration rate and albuminuria with all‐cause and cardiovascular mortality in general population cohorts: A collabora‐

[12] Matsushita K. et al. Estimated glomerular filtration rate and albuminuria for predic‐ tion of cardiovascular outcomes: A collaborative meta‐analysis of individual participant

[13] Meguid El Nahas A, Bello AK. Chronic kidney disease: The global challenge. Lancet.

tional study. Journal of the Pakistan Medical Association. 2015;**65**(4):366‐369

## **12. Conclusion**

Renal transplantation is the single most effective intervention for reducing CV risk in appro‐ priately selected patients with ESRD. Even though renal transplant has significantly improved survival for successful recipients, CVD remains the leading cause of death in patients with functional grafts [107].

In addition to traditional CVD risk factors, RT patients develop specific risk factors related to ESRD including but not limited to left ventricular hypertrophy, over‐activation of the sympa‐ thetic nervous system, pro‐inflammatory state, and proteinuria.

Post‐transplantation, patients are maintained on a regimen of immunosuppressive medica‐ tions. Even though immunosuppressive drugs have not been directly associated with car‐ diovascular events, they play pivotal role in risk associated with traditional risk factors of hypertension, dyslipidemia, and diabetes.

Strategies targeting transplant‐specific CV risk factors should include optimization of renal function, limiting risk of rejection, avoidance of PTDM and anticipation of CV side effects of immunosuppression.

## **Author details**

Ali Osama Malik1 , Sumit Sehgal2 , Hashim Hussnain Ahmed<sup>3</sup> , Subodh Devabhaktuni2 , Edward Co1 , Arhama Aftab Malik5 , Syed Shah4 and Chowdhury Ahsan2 \*

\*Address all correspondence to<EMAIL_ADDRESS>
1 Department of Internal Medicine, University of Nevada, School of Medicine, Reno, Nevada

2 Department of Cardiovascular Medicine, University of Nevada, School of Medicine, Reno, Nevada

3 Department of Surgery, Shaukat Khanum Memorial Cancer and Research Center, Pakistan

4 Kidney Specialist of Southern Nevada, Nevada, USA

5 Aga Khan University, Karachi, Pakistan

## **References**

**11.2. Calcineurin inhibitors**

**12. Conclusion**

functional grafts [107].

immunosuppression.

**Author details**

Ali Osama Malik1

Edward Co1

Nevada

cyclosporine may lead to improvement in PTDM.

120 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

thetic nervous system, pro‐inflammatory state, and proteinuria.

hypertension, dyslipidemia, and diabetes.

, Sumit Sehgal2

\*Address all correspondence to<EMAIL_ADDRESS>
4 Kidney Specialist of Southern Nevada, Nevada, USA

5 Aga Khan University, Karachi, Pakistan

, Arhama Aftab Malik5

In patients receiving cyclosporine combined with mycophenolate mofetil, a 50% reduction in cyclosporine dose or complete cyclosporine withdrawal from a mycophenolate mofetil or sirolimus‐based regimen results in fewer anti‐hypertensive medications [106]. Tacrolimus increases the risk of PTDM more than cyclosporine, therefore, switching from tacrolimus to

Renal transplantation is the single most effective intervention for reducing CV risk in appro‐ priately selected patients with ESRD. Even though renal transplant has significantly improved survival for successful recipients, CVD remains the leading cause of death in patients with

In addition to traditional CVD risk factors, RT patients develop specific risk factors related to ESRD including but not limited to left ventricular hypertrophy, over‐activation of the sympa‐

Post‐transplantation, patients are maintained on a regimen of immunosuppressive medica‐ tions. Even though immunosuppressive drugs have not been directly associated with car‐ diovascular events, they play pivotal role in risk associated with traditional risk factors of

Strategies targeting transplant‐specific CV risk factors should include optimization of renal function, limiting risk of rejection, avoidance of PTDM and anticipation of CV side effects of

, Hashim Hussnain Ahmed<sup>3</sup>

and Chowdhury Ahsan2

, Syed Shah4

1 Department of Internal Medicine, University of Nevada, School of Medicine, Reno, Nevada 2 Department of Cardiovascular Medicine, University of Nevada, School of Medicine, Reno,

3 Department of Surgery, Shaukat Khanum Memorial Cancer and Research Center, Pakistan

, Subodh Devabhaktuni2

\*

,

[14] Denker M. et al. Chronic Renal Insufficiency Cohort Study (CRIC): Overview and Summary of Selected Findings. Clinical Journal of the American Society of Nephrology. 2015;**10**(11):2073‐2083

[28] Gutierrez OM. et al. Fibroblast growth factor 23 and mortality among patients undergo‐ ing hemodialysis. The New England Journal of Medicine. 2008;**359**(6):584‐592

Cardiovascular Aspects of Patients with Chronic Kidney Disease and End-Stage Renal Disease

http://dx.doi.org/10.5772/intechopen.69294

123

[29] Isakova T. et al. Fibroblast growth factor 23 and risks of mortality and end‐stage renal disease in patients with chronic kidney disease. Jama. 2011;**305**(23):2432‐2439

[30] Sarnak MJ. et al. Kidney disease as a risk factor for development of cardiovascu‐ lar disease: A statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and

[31] Manske CL. et al. Coronary revascularisation in insulin‐dependent diabetic patients

[32] Best PJ. et al. The impact of renal insufficiency on clinical outcomes in patients undergo‐ ing percutaneous coronary interventions. Journal of the American College of Cardiology.

[33] Kahn JK. et al. Short‐ and long‐term outcome of percutaneous transluminal coronary angioplasty in chronic dialysis patients. American Heart Journal. 1990;**119**(3 Pt 1):484‐489

[34] Malyszko J. et al. Hemostasis, platelet function and serotonin in acute and chronic renal

[35] Di Minno G. et al. Platelet dysfunction in uremia. Multifaceted defect partially corrected

[36] Soslau G. et al. Selective reduction of serotonin storage and ATP release in chronic renal failure patients platelets. American Journal of Hematology. 1990;**35**(3):171‐178

[37] Gordge MP. et al. Platelet function and the bleeding time in progressive renal failure.

[38] Mezzano D. et al. Hemostatic disorder of uremia: The platelet defect, main determinant of the prolonged bleeding time, is correlated with indices of activation of coagulation

[39] Mezzano D. et al. Endothelial cell markers in chronic uremia: Relationship with hemo‐ static defects and severity of renal failure. Thrombosis Research. 1997;**88**(6):465‐472 [40] Reddan D. et al. Anticoagulation in acute cardiac care in patients with chronic kidney

[41] Schoebel FC. et al. Restenosis after elective coronary balloon angioplasty in patients with end stage renal disease: A case‐control study using quantitative coronary angiography.

[42] Le Feuvre C. et al. Comparison of clinical outcome following coronary stenting or balloon angioplasty in dialysis versus non‐dialysis patients. American Journal of Cardiology.

Epidemiology and Prevention. Circulation. 2003;**108**(17):2154‐2169

with chronic renal failure. Lancet. 1992;**340**(8826):998‐1002

failure. Thrombosis Research. 1996;**83**(5):351‐361

Thromb Haemost. 1988;**60**(1):83‐87

Heart. 1997;**78**(4):337‐342

2000;**85**(11):1365‐1368

by dialysis. American Journal of Medicine. 1985;**79**(5):552‐559

and fibrinolysis. Thrombosis and Haemostasis. 1996;**76**(3):312‐321

disease. American Heart Journal. 2003;**145**(4):586‐594

2002;**39**(7):1113‐1119

[28] Gutierrez OM. et al. Fibroblast growth factor 23 and mortality among patients undergo‐ ing hemodialysis. The New England Journal of Medicine. 2008;**359**(6):584‐592

[14] Denker M. et al. Chronic Renal Insufficiency Cohort Study (CRIC): Overview and Summary of Selected Findings. Clinical Journal of the American Society of Nephrology.

[15] Zhang L. et al. Prevalence of chronic kidney disease in China: A cross‐sectional survey.

[16] Rahman M. et al. Association between chronic kidney disease progression and car‐ diovascular disease: Results from the CRIC Study. American Journal of Nephrology.

[17] Iimori S. et al. Anaemia management and mortality risk in newly visiting patients with chronic kidney disease in Japan: The CKD‐ROUTE study. Nephrology (Carlton).

[18] Martinez‐Castelao A. et al. Baseline characteristics of patients with chronic kidney disease stage 3 and stage 4 in Spain: The MERENA observational cohort study. BMC

[19] Yuan J. et al. Prevalence and risk factors for cardiovascular disease among chronic kidney disease patients: Results from the Chinese cohort study of chronic kidney disease

[20] Shlipak MG. et al. Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. Annals of Internal Medicine. 2002;**137**(7):

[21] Go AS. et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. The New England Journal of Medicine. 2004;**351**(13):1296‐1305

[22] van der Velde M. et al. Lower estimated glomerular filtration rate and higher albumin‐ uria are associated with all‐cause and cardiovascular mortality. A collaborative meta‐ analysis of high‐risk population cohorts. Kidney International. 2011;**79**(12):1341‐1352

[23] Manjunath G. et al. Level of kidney function as a risk factor for cardiovascular outcomes

[24] Chonchol M. et al. Chronic kidney disease is associated with angiographic coronary

[25] Chin CY. et al. Coronary plaque characteristics in hemodialysis‐dependent patients as assessed by optical coherence tomography. American Journal of Cardiology. 2017;**119**

[26] Farzaneh‐Far A. Morphology of coronary atherosclerotic lesions in patients with end‐

[27] Nakano T. et al. Association of kidney function with coronary atherosclerosis and calcifi‐ cation in autopsy samples from Japanese elders: The Hisayama study. American Journal

stage renal failure. Nephrology Dialysis Transplantation. 2000;**15**(10):1710

2015;**10**(11):2073‐2083

2014;**40**(5):399‐407

2015;**20**(9):601‐608

555‐562

Nephrology. 2011;**12**:53

(C‐STRIDE). BMC Nephrology. 2017;**18**(1):23

in the elderly. Kidney International. 2003;**63**(3):1121‐1129

of Kidney Diseases. 2010;**55**(1):21‐30

artery disease. American Journal of Nephrology. 2008;**28**(2):354‐360

Lancet. 2012;**379**(9818):815‐822

122 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

[43] Labrousse L. et al. Early and long term results of coronary artery bypass grafts in patients with dialysis dependent renal failure. European Journal of Cardio‐Thoracic Surgery. 1999;**15**(5):691‐696

[56] Chiu DY. et al. Cardiac imaging in patients with chronic kidney disease. Nature Reviews

Cardiovascular Aspects of Patients with Chronic Kidney Disease and End-Stage Renal Disease

http://dx.doi.org/10.5772/intechopen.69294

125

[57] Ali ZA. et al. Imaging‐ and physiology‐guided percutaneous coronary intervention without contrast administration in advanced renal failure: A feasibility, safety, and out‐

[58] Detrenis S. et al. Lights and shadows on the pathogenesis of contrast‐induced nephropa‐ thy: State of the art. Nephrology Dialysis Transplantation. 2005;**20**(8):1542‐1550

[59] Persson PB, Hansell P,Liss P. Pathophysiology of contrast medium‐induced nephropathy.

[60] Cantley LG. et al. Role of endothelin and prostaglandins in radiocontrast‐induced renal

[61] Katholi RE. et al. Nephrotoxicity from contrast media: Attenuation with theophylline.

[62] Russo D. et al. Early effects of contrast media on renal hemodynamics and tubu‐ lar function in chronic renal failure. Journal of the American Society of Nephrology.

[63] Cigarroa RG. et al. Dosing of contrast material to prevent contrast nephropathy in patients with renal disease. American Journal of Medicine. 1989;**86**(6 Pt 1):649‐652 [64] Rudnick MR. et al. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: A randomized trial. The Iohexol cooperative study. Kidney International.

[65] Karimi Galougahi K. et al. Zero‐contrast percutaneous coronary intervention on calci‐ fied lesions facilitated by rotational atherectomy. Catheterization and Cardiovascular

[66] Freda BJ. et al. Cardiac troponins in renal insufficiency: Review and clinical implications.

[67] Thygesen K. et al. Third universal definition of myocardial infarction. Circulation.

[68] Alcalai R. et al. Acute coronary syndrome vs nonspecific troponin elevation: Clinical predictors and survival analysis. Archives of Internal Medicine. 2007;**167**(3):276‐281 [69] Giannitsis E, Katus HA. Cardiac troponin level elevations not related to acute coronary

[70] Cardinaels EP. et al. High‐sensitivity cardiac troponin concentrations in patients with chest discomfort: Is it the heart or the kidneys as well? PLoS One. 2016;**11**(4):e0153300

[71] Mair J. et al. Serum cardiac troponin T after extraordinary endurance exercise. Lancet.

Journal of the American College of Cardiology. 2002;**40**(12):2065‐2071

syndromes. Nature Reviews Cardiology. 2013;**10**(11):623‐634

come study. European Heart Journal. 2016;**37**(40):3090‐3095

artery constriction. Kidney International. 1993;**44**(6):1217‐1223

Nephrology. 2015;**11**(4):207‐220

Kidney International. 2005;**68**(1):14‐22

Radiology. 1995;**195**(1):17‐22

1995;**6**(5):1451‐1458

1995;**47**(1):254‐261

Interventions. 2017

2012;**126**(16):2020‐2035

1992;**340**(8826):1048

[56] Chiu DY. et al. Cardiac imaging in patients with chronic kidney disease. Nature Reviews Nephrology. 2015;**11**(4):207‐220

[43] Labrousse L. et al. Early and long term results of coronary artery bypass grafts in patients with dialysis dependent renal failure. European Journal of Cardio‐Thoracic Surgery.

[44] Horst M. et al. Cardiac surgery in patients with end‐stage renal disease: 10‐year experience.

[45] Anderson RJ. et al. Renal failure predisposes patients to adverse outcome after coro‐ nary artery bypass surgery. VA Cooperative Study #5. Kidney International. 1999;**55**(3):

[46] Szczech LA. et al. Differential survival after coronary revascularization procedures among patients with renal insufficiency. Kidney International. 2001;**60**(1):292‐299

[47] Marui A. et al. Percutaneous coronary intervention versus coronary artery bypass grafting in patients with end‐stage renal disease requiring dialysis (5‐year outcomes of the CREDO‐Kyoto PCI/CABG Registry Cohort‐2). American Journal of Cardiology.

[48] Bangalore S. et al. Revascularization in patients with multivessel coronary artery dis‐ ease and chronic kidney disease: Everolimus‐eluting stents versus coronary artery bypass graft surgery. Journal of the American College of Cardiology. 2015;**66**(11):

[49] Raggi P, Alexopoulos N. Cardiac imaging in chronic kidney disease patients. Seminars

[50] Sharma R. et al. Dobutamine stress echocardiography and cardiac troponin T for the detection of significant coronary artery disease and predicting outcome in renal trans‐