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Inflammation in chronic kidney disease: role in the progression of renal and cardiovascular disease

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Abstract

Inflammation is the response of the vasculature or tissues to various stimuli. An acute and chronic pro-inflammatory state exists in patients with chronic kidney disease (CKD), contributing substantially to morbidity and mortality. There are many mediators of inflammation in adults with CKD and end-stage kidney disease (ESKD), including hypoalbuminemia/malnutrition, atherosclerosis, advanced oxidation protein products, the peroxisome proliferators-activated receptor, leptin, the thiobarbituric acid reactive system, asymmetric dimethyl arginine, iron, fetuin-A, and cytokines. Inflammation contributes to the progression of CKD by inducing the release of cytokines and the increased production and activity of adhesion molecules, which together contribute to T cell adhesion and migration into the interstitium, subsequently attracting pro-fibrotic factors. Inflammation in CKD also causes mortality from cardiovascular disease by contributing to the development of vascular calcifications and endothelial dysfunction. Similar to the situation in adults, cardiovascular disease in pediatric CKD is linked to inflammation: abnormal left ventricular wall geometry is positively associated with markers of inflammation. This review focuses on traditional and novel mediators of inflammation in CKD and ESKD, and the deleterious effect inflammation has on the progression of renal and cardiovascular disease.

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References

  1. Mitchell RN, Cotran RS (1998) Acute and chronic inflammation. In: Cotran RS, Kumar V, Collins T, Robbins SL (eds) Robbins pathologic basis of disease, 6th edn. Elsevier Science Health Science/W.B. Saunders, Philadelphia, pp 50–88

    Google Scholar 

  2. Horl WH (2002) Hemodialysis membranes: Interleukins, biocompatibility, and middle molecules. J Am Soc Nephrol 13[Suppl 1]:S62–S71

    CAS  PubMed  Google Scholar 

  3. Hricik DE, Schulak JA, Sell DR, Fogarty JF, Monnier VM (1993) Effects of the kidney or kidney-pancreas transplantation on plasma pentosidine. Kidney Int 43:398–403

    CAS  PubMed  Google Scholar 

  4. Alhamdani MS (2005) Impairment of glutathione biosynthetic pathway in uraemia and dialysis. Nephrol Dial Transplant 20:124–128

    CAS  PubMed  Google Scholar 

  5. Massola Shimizu M, Coimbra TL, De Araujo M, Menezes LF, Seguro AC (2005) N-acetylcysteine attenuates the progression of chronic renal failure. Kidney Int 68:2208–2217

    Google Scholar 

  6. Witko-Sarsat V, Friedlander M, Nguyen-Khoa T, Capeillère-Blandin C, Nguyen AT, Canteloup S, Dayer JM, Jungers P, Drüeke T, Descamps-Latscha B (1998) Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol 161:2524–2532

    CAS  PubMed  Google Scholar 

  7. Yao Q, Nordfors L, Axelsson J, Heimbürger O, Qureshi AR, Báràny P, Lindholm B, Lönnqvist F, Schalling M, Stenvinkel P (2005) Peroxisome proliferators-activated receptor γ polymorphisms affect systemic inflammation and survival in end-stage renal disease patients starting renal replacement therapy. Atherosclerosis 182:105–111

    CAS  PubMed  Google Scholar 

  8. Mallamaci F, Tripepi G, Zoccali C (2005) Leptin in end stage renal disease (ESRD): A link between fat mass, bone, and the cardiovascular system. J Nephrol 18:464–468

    CAS  PubMed  Google Scholar 

  9. Gönenc A, Atak Y, Orman M, Simşek B (2002) Lipid peroxidation and antioxidant systems in hemodialyzed patients. Nephrol Dial Transplant 31:88–96

    Google Scholar 

  10. Agarwal R (2006) Proinflammatory effects of iron sucrose in chronic kidney disease. Kidney Int 69:1259–1263

    CAS  PubMed  Google Scholar 

  11. Pereira BJ, Shapiro L, King AJ, Falagas ME, Strom JA, Dinarello CA (1994) Plasma levels of IL-1 beta, TNF alpha and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients. Kidney Int 45:890–896

    CAS  PubMed  Google Scholar 

  12. Kimmel PL, Phillips TM, Simmens SJ, Peterson RA, Wiehs KL, Alleyne S, Cruz I, Yanovski JA, Veis JH (1998) Immunologic function and survival in hemodialysis patients. Kidney Int 54:236–244

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Costa E, Lima M, Alves JM, Rocha S, Rocha-Pereira P, Castro E, Miranda V, Faria MD, Loureiro A, Quintanilha A, Belo L, Santos-Silva A (2008) Inflammation, T-Cell phenotype, and inflammatory cytokines in chronic kidney disease patients under hemodialysis and its relationship to resistance to recombinant human erythropoietin therapy. J Clin Immunol 28:268–275

    CAS  PubMed  Google Scholar 

  14. Nairn J, Hodge G, Henning P (2005) Changes in leukocyte subsets: clinical implications for children with chronic renal failure. Pediatr Nephrol 20:190–196

    PubMed  Google Scholar 

  15. Goldstein SL, Currier H, Waters L, Hempe JM, Sheth RD, Silverstein DM (2003) Acute and chronic inflammation in pediatric patients receiving hemodialysis. J Pediatr 143:653–657

    CAS  PubMed  Google Scholar 

  16. Goldstein SL, Leung JC, Silverstein DM (2006) Pro and anti-inflammatory cytokines in chronic pediatric dialysis patients: effect of aspirin. Clin J Am Soc Nephrol 1:979–986

    CAS  PubMed  Google Scholar 

  17. Cengiz N, Baskin E, Agras PI, Sezgin N, Saatci U (2005) Relationship between chronic inflammation and cardiovascular risk factors in children on maintenance hemodialysis. Transplant Proc 37:2915–2917

    CAS  PubMed  Google Scholar 

  18. Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ (2005) Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependant pathway. Biochem Biophys Res Commun 334:1092–1101

    CAS  PubMed  Google Scholar 

  19. Nüsken K-D, Kratzsch J, Wienholz V, Stöhr W, Rascher W, Dötsch J (2006) Circulating resistin concentrations in children depend on renal function. Nephrol Dial Transplant 21:107–112

    PubMed  Google Scholar 

  20. Sebeková K, Podracká L, Blazícek P, Syrová D, Heidland A, Schinzel R (2001) Plasma levels of advanced glycation end products in children with renal disease. Pediatr Nephrol 16:1105–1112

    PubMed  Google Scholar 

  21. Pavlova EL, Lilova MI, Savov VM (2005) Oxidative stress in children with kidney disease. Pediatr Nephrol 20:1599–1604

    PubMed  Google Scholar 

  22. Bolton CH, Downs LG, Victory JG, Dwight JF, Tomson CR, Mackness MI, Pinkney JH (2001) Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines. Nephrol Dial Transplant 16:1189–1197

    CAS  PubMed  Google Scholar 

  23. Verma S, Badiwala MV, Weisel RD, Li SH, Wang CH, Fedak PW, Li RK, Mickle DA (2003) C-reactive protein activates the nuclear factor-kappaB signal transduction pathway in saphenous vein endothelial cells: implications for atherosclerosis and restenosis. J Thorac Cardiovasc Surg 126:1886–1891

    CAS  PubMed  Google Scholar 

  24. Verma S, Wang CH, Li SH, Dumont AS, Fedak PW, Badiwala MV, Dhillon B, Weisel RD, Li RK, Mickle DA, Stewart DJ (2002) A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 106:913–919

    CAS  PubMed  Google Scholar 

  25. Nath KD (1992) Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis 20:1–17

    CAS  Google Scholar 

  26. Hill PA, Lan HY, Nikolic-Paterson DJ, Atkins RC (1994) ICAM-1 directs migration and localization of intersitial leukocytes in experimental glomerulonephritis. Kidney Int 45:32–42

    CAS  PubMed  Google Scholar 

  27. Lebleu VS, Sugimoto H, Miller CA, Gattone VH 2nd, Kalluri R (2008) Lymphocytes are dispensable for glomerulonephritis but required for renal interstitial fibrosis in matrix defect-induced Alport renal disease. Lab Invest 88:284–292

    CAS  PubMed  Google Scholar 

  28. Abbate M, Zoja C, Corna D, Capitanio M, Bertani T, Remuzzi G (1998) In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation. J Am Soc Nephrol 9:1213–1224

    CAS  PubMed  Google Scholar 

  29. Zoccali C, Maas R, Cutrupi S, Pizzini P, Finocchiaro P, Cambareri F, Panuccio V, Martorano C, Schulze F, Enia G, Tripepi G, Boger R (2007) Asymmetric dimethyl-arginine (ADMA) response to inflammation in acute infections. Nephrol Dial Transplant 22:801–806

    CAS  PubMed  Google Scholar 

  30. Kielstein JT, Boger RH, Bode-Boger SM, Schäffer J, Barbey M, Koch KM, Frölich JC (1999) Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol 10:594–600

    CAS  PubMed  Google Scholar 

  31. Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Böhm R, Metzger T, Wanner C, Jahnen-Dechent W, Floege J (2003) Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361:827–833

    CAS  PubMed  Google Scholar 

  32. Panzer U, Schneider A, Steinmetz OM, Wenzel U, Barth P, Reinking R, Becker JU, Harendza S, Zahner G, Fischereder M, Krämer BK, Schlöndorff D, Ostendorf T, Floege J, Helmchen U, Stahl RA (2005) The chemokine receptor 5 Delta32 mutation is associated with increased renal survival in patients with IgA nephropathy. Kidney Int 67:75–81

    CAS  PubMed  Google Scholar 

  33. Berthoux FC, Berthoux P, Mariat C, Thibaudin L, Afiani A, Linossier MT (2006) CC-chemokine receptor five gene polymorphism in primary IgA nephropathy: the 32 bp deletion allele is associated with late progression to end-stage renal failure with dialysis. Kidney Int 69:565–572

    CAS  PubMed  Google Scholar 

  34. Liao TD, Yang XP, Liu YH, Shesely EG, Cavasin MA, Kuziel WA, Pagano PJ, Carretero OA (2008) Role of inflammation in the development of renal damage and dysfunction in angiotensin II-induced hypertension. Hypertension 52:256–263

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ishidoya S, Morrissey J, McCracken R, Reyes A, Klahr S (1995) Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int 47:1285–1294

    CAS  PubMed  Google Scholar 

  36. Diamond JR (1991) Analogous pathobiologic mechanisms in glomerulosclerosis and atherosclerosis. Kidney Int 39[Suppl]:S29–S34

    Google Scholar 

  37. Fried L, Solomon C, Shlipak M, Seliger S, Stehman-Breen C, Bleyer AJ, Chaves P, Furberg C, Kuller L, Newman A (2004) Inflammatory and prothrombotic markers and the progression of renal disease in elderly individuals. J Am Soc Nephrol 15:3184–3191

    PubMed  Google Scholar 

  38. Sarnak MJ, Poindexter A, Wang SR, Beck GJ, Kusek JW, Marcvina SM, Greene T, Levey AS (2002) Serum C-reactive protein and leptin as predictors of kidney disease progression in the Modification of Diet in Renal Disease Study. Kidney Int 62:2208–2215

    CAS  PubMed  Google Scholar 

  39. Yu C, Gong R, Rifai A, Tolbert EM, Dworkin LD (2007) Long-term, high-dosage candesartan suppresses inflammation and injury in chronic kidney disease: nonhemodynamic renal protection. J Am Soc Nephrol 18:750–759

    CAS  PubMed  Google Scholar 

  40. Kunz R, Friedrich C, Wolbers M, Mann JF (2008) Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 148:30–48

    PubMed  Google Scholar 

  41. Goicoechea M, de Vinuesa SG, Lahera V, Cachofeiro V, Gómez-Campderá F, Vega A, Abad S, Luño J (2006) Effects of atorvastatin on inflammatory and fibrinolytic parameters in patients with chronic kidney disease. J Am Soc Nephrol 17:S231–S235

    CAS  PubMed  Google Scholar 

  42. Quiroz Y, Ferrebuz A, Romero F, Vaziri ND, Rodriguez-Iturbe B (2008) Melatonin ameliorates oxidative stress, inflammation, proteinuria, and progression of renal damage in rats with renal mass reduction. Am J Physiol 294:F336–344

    CAS  Google Scholar 

  43. Tu X, Chen X, Xie Y, Shi S, Wang J, Chen Y, Li J (2008) Anti-inflammatory renoprotective effect of clopidogrel and irbesartan in chronic renal injury. J Am Soc Nephrol 19:77–83

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Schlondorff D (1987) The glomerular mesangial cell: an expanding role for a specialized pericyte. FASEB J 1:272–281

    CAS  PubMed  Google Scholar 

  45. Zu N, Li P, Li N, Choy P, Gong Y (2007) Mechanism of saikosaponin-d in the regulation of rat mesangial cell proliferation and synthesis of extracellular matrix proteins. Biochem Cell Biol 85:169–174

    CAS  PubMed  Google Scholar 

  46. Gong R, Rifai A, Dworkin LD (2006) Anti-inflammatory effect of hepatocyte growth factor in chronic kidney disease: targeting the inflamed vascular endothelium. J Am Soc Nephrol 17:2464–2473

    CAS  PubMed  Google Scholar 

  47. Sankaran D, Bankovic-Calic N, Ogborn MR, Crow G, Aukema HM (2007) Selective COX-2 inhibition markedly slows disease progression and attenuates altered prostanoid production in Han:SPRD-cy rats with inherited kidney disease. Am J Physiol 293:F821–F830

    CAS  Google Scholar 

  48. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH (1998) Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 98:731–733

    CAS  PubMed  Google Scholar 

  49. Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C (1999) Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 55:648–658

    CAS  PubMed  Google Scholar 

  50. Schwarz U, Buzello M, Ritz E, Stein G, Raabe G, Wiest G, Mall G, Amann K (2000) Morphology of coronary artery atherosclerotic lesions in patients with end-stage renal failure. Nephrol Dial Transplant 15:218–223

    CAS  PubMed  Google Scholar 

  51. Landray M, Wheeler D, Lip GY, Nwman DJ, Blann AD, McGlynn FJ, Ball S, Townend JN, Baigent C (2004) Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: The Chronic Renal Impairment in Birmingham (CRIB) Study. Am J Kidney Dis 43:244–253

    CAS  PubMed  Google Scholar 

  52. Morris ST, Jardine AG (2000) The vascular endothelium in chronic renal failure. J Nephrol 13:96–105

    CAS  PubMed  Google Scholar 

  53. Mallamaci F, Tripepi G, Cutrupi S, Malatino LS, Zoccali C (2005) Prognostic value of combined use of biomarkers of inflammation, endothelial dysfunction, and myocardiopathy in patients with ESRD. Kidney Int 67:2330–2337

    CAS  PubMed  Google Scholar 

  54. Annuk M, Soveri I, Zilmer M, Lind L, Hulthe J, Fellström B (2005) Endothelial function, CRP and oxidative stress in chronic kidney disease. J Nephrol 18:721–726

    CAS  Google Scholar 

  55. Pandolfi A, Di Pietro N, Sirolli V, Giardinelli A, Di Silvestre S, Amoroso L, Di Tomo P, Capani F, Consoli A, Bonomini M (2007) Mechanisms of uremic erythrocyte-induced adhesion of human monocytes to cultured endothelial cells. J Cell Physiol 213:699–709

    CAS  PubMed  Google Scholar 

  56. Foley RN, Parfrey PS, Sarnak MJ (1998) Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 9:s16–s23

    CAS  PubMed  Google Scholar 

  57. Groothoff JW, Gruppen MP, Offringa M, Hutten J, Lilien MR, Van De Kar NJ, Wolff ED, Davin JC, Heymans HS (2002) Mortality and causes of death of end-stage renal disease in children: a Dutch cohort study. Kidney Int 61:621–629

    Google Scholar 

  58. Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U, Mehls O, Schaefer F (2002) Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 106:100–105

    Google Scholar 

  59. Mitsnefes M, Ho PL, McEnerey PT (2003) Hypertension and progression of chronic renal insufficiency in children: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). J Am Soc Nephrol 14:2618–2622

    PubMed  Google Scholar 

  60. Mitsnefes MM, Kimball TR, Border WL, Witt SA, Glascock BJ, Khoury PR, Daniels SR (2004) Impaired left ventricular diastolic function in children with chronic renal failure. Kidney Int 65:1461–1466

    PubMed  Google Scholar 

  61. Matteucci MC, Wühl E, Picca S, Mastrostefano A, Rinelli G, Romano C, Rizzoni G, Mehls O, De Simone G, Schaefer F, ESCAPE Trial Group (2006) Left ventricular geometry in children with mild to moderate chronic renal insufficiency. J Am Soc Nephrol 17:218–226

    PubMed  Google Scholar 

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Silverstein, D.M. Inflammation in chronic kidney disease: role in the progression of renal and cardiovascular disease. Pediatr Nephrol 24, 1445–1452 (2009). https://doi.org/10.1007/s00467-008-1046-0

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