Role of High-sensitivity C-reactive Protein as a Marker of Inflammation in Pre-dialysis Patients of Chronic Renal Failure

Transcription

1 ORIGINAL ARTICLE JIACM 2009; 10(1 & 2): Abstract Role of High-sensitivity C-reactive Protein as a Marker of Inflammation in Pre-dialysis Patients of Chronic Renal Failure N Nand*, HK Aggarwal**, RK Yadav***, A Gupta****, M Sharma***** Introduction: Chronic inflammation is a major contributor to increased mortality and morbidity in end-stage renal disease (ESRD). The odds of cardiovascular disease (CVD) have been found to be 1.7 times greater in these cases. High-sensitivity CRP (hs-crp) has been reported to be the most powerful clinical marker of malnutrition and it also interacts with the haematopoietic system at several levels resulting in reduced haemoglobin levels. The aim of the present study was to analyse the evolution of pre-dialysis population of chronic kidney disease according to their basal levels of hs-crp. Material and methods: Forty pre-dialysis adult patients of ESRD with creatinine clearance in the range of 4-20 ml/min were included. Patients were divided into two groups. Those with hs-crp < 6 mg/dl were placed in group I and with hs-crp > 6 mg/dl in group II. The patients were followed for 6 months. Results: 40% of cases had an elevated level of hs-crp (mean mg/dl). Response to erythropoietin was blunted and the incidence of cardiovascular events was increased in patients with high values of hs-crp. Haemoglobin, serum albumin and BMI (body mass index) were significantly higher in patients having low hs-crp (p < 0.001, p < 0.05). No patient with low hs-crp required dialysis, whereas 88.75% of patients in high hs-crp group required haemodialysis (p < 0.001). Conclusion: A substantial number of patients of ESRD had elevated levels of hs-crp which was associated with poor clinical outcome including low haemoglobin, hypo-responsiveness to erythropoietin therapy, poor nutritional status, low albumin levels, greatly increased risk of cardiovascular disease, and frequent and early need of haemodialysis. Key words: End-stage renal disease, cardiovascular disease, erythropoietin, haemodialysis. Introduction Despite a rapid improvement in dialysis technology during the last 20 years, morbidity and mortality rates remain quite high for patients of ESRD 1. Cardiovascular disease remains the major cause of mortality in ESRD and hs-crp has been the strongest predictor of cardiovascular and all cause mortality in these patients 2. Since protein and calorie malnutrition occurs commonly in these patients, therefore serum albumin concentration has been widely used as the best clinical marker of malnutrition and has been touted to be the most concerning link between malnutrition and mortality. It has been documented that the level of inflammation as assessed by major acute phase proteins like hs-crp was the most powerful factor in predicting serum albumin levels 3. Inflammation and acute phase response also interact with the haematopoetic system at several levels resulting in reduced erythropoiesis, accelerated destruction of erythrocytes and blunting of the reactive increase in erythropoietin in response to reduced haemoglobin levels 4. Therefore much interest has been focused on inflammation, the secret killer in ESRD that promotes atherosclerosis, malnutrition, and anaemia in this group of patients. Factors responsible for augmented inflammatory response in ESRD include accumulation of proinflammatory compounds, decreased clearance of cytokines, atherosclerosis per se, unrecognised persistent infections, and the dialysis procedure per se. The new clinical meaning of hs-crp in ESRD patients is that of an index that reflects their overall health state as determined by several conditions. It shows the grade of their health aggravation mainly by renal insufficiency and its complications. The accurate assessment of hs-crp gives us an estimation of the overall health status during the period of the measurement 5. A high value indicates an unfavourable condition aggravated by renal insufficiency and its complications, while a lower one should show a * Senior Professor and Head, ** Professor, *** Assistant Professor, **** Senior Resident, Department of Medicine and Nephrology, ***** Professor of Biochemistry, Pt. B.D. Sharma Post-graduate Institute of Medical Sciences, Rohtak , Haryana.

2 relatively good condition of their health 6. The significance of hs-crp levels in ESRD patients has not been studied extensively 7. The aim of the present study is to analyse the evolution of a pre-dialysis population according to their basal levels of hs-crp. Material and methods A total of 40 pre-dialysis adult patients of chronic renal failure with creatinine clearance in the range of 4-20 ml/min were included. A pre-informed consent was obtained. Patients suffering from acute or chronic infections, previous coronary vascular disease, pancreatitis, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, psoriasis, or patients of burns, trauma, or who had undergone a recent surgery were excluded. The cohort of patient was followed for 6 months after initial measurement of hs-crp levels. Cutoff level of 0.6 mg/dl was used as an indicator of high levels of hs-crp 8. Patients were divided into two groups, depending upon their hs-crp levels at baseline being higher or lower than 0.6 mg/dl. All patients were prescribed diet containing approximately 0.6 gm/kg/day of protein and erythropoietin was prescribed for haemoglobin level below g/dl. hs-crp concentrations were determined using latex-enhanced immunonephelometric assays 7. During the study, patients were evaluated two monthly. On each visit, patients were examined and investigated thoroughly and findings were recorded. The data obtained during follow-up was compared between low and high hs-crp groups and its prognostic significance was analysed. Results The mean age of patients was ± years. There were 22 men and 18 women. 30% of patients were suffering from chronic glomerulonephritis, followed by hypertensive nephropathy (22.5%), obstructive uropathy (17.5%), diabetic nephropathy (15%), ischaemic nephropathy (7.5%), adult polycystic kidney disease (5%), and renal amyloidosis (2.5%). The average baseline CRP was 2.06 ± 1.82 mg/dl. 40% patients had an elevated level of hs-crp while 60% patients had hs-crp value below 0.6 mg/dl. On comparing the 2 groups haemoglobin levels were found to be significantly higher (p < 0.001) in low hs-crp group both at baseline as well as after 6 months (Table I, Fig. 1). Patients with elevated hs-crp levels had lower haemoglobin and they continued to be more anaemic on follow-up. Response to erythropoietin was also blunted in patients with high hs-crp levels (group II). The values of erythropoietin/haemoglobin ratio at baseline as well as after six months of therapy in group I patients were 0.56 ± 0.10 and 0.44 ± 0.07 respectively while in group II patients the values were 0.62 ± 0.13 and 0.53 ± Though at baseline, the difference was not significant, it was significantly higher in group II at the end of 6 months (p < 0.05) (Table I, Fig. 1). The incidence of cardiovascular events was increased in patients with high values of hs-crp. It was noticed in this study that 50% of the patients in group II had cardiovascular disease during the study period of 6 months. This was significantly different as compared to group I where only 2 patients had ischaemic episodes (p < 0.01) (Table I). Serum albumin levels were not significantly different at baseline in the two groups (p > 0.05). But at the end of the study, group I had significantly higher albumin than group II, (p < 0.001). Similarly, body mass index was also significantly higher in patients having low hs-crp at the end of the study (p < 0.05) (Table I, Fig. 1). Parameters Time in months BMI (Group 1) BMI (Group 2) Hb (Group 1) Hb (Group 2) S. Alb (Group 1) S. Alb (Group 2) Epo/Hb (Group 1) Epo/Hb (Group 2) Fig. 1: Evolution of haemoglobin, serum albumin, body mass index, and erythropoietin response in the two groups. Journal, Indian Academy of Clinical Medicine Vol. 10, No. 1 & 2 January-June,

3 The clinical course of patients with high hs-crp levels was poorer as they required early and repeated admissions for haemodialysis. In this study, no patient with low hs- CRP level required dialysis, whereas 88.75% of patients in high hs-crp (group II) required haemodialysis during the six months of study (p < 0.001). include impaired renal clearance of cytokines, accumulation of advanced glycation end-products (AGEs), atherosclerosis per se, other inflammatory diseases and unrecognised persistent infections. In addition, the dialysis procedure per se has been linked to an increased risk of inflammation 10. Table I: Evolution of haemoglobin, erythropoietin response, serum albumin, body mass index, and cardiovascular events in the two groups. Parameter Group I P value Group II P value P value (Paired t-test) (Paired t-test) (Unpaired t-test) Haemoglobin (g%) A 7.35 ± 1.41 < ± 1.22 > 0.05 > 0.05 B 9.22 ± ± 1.07 < EPO/Hb ratio A 0.56 ± 0.10 < ± 0.13 > 0.05 > 0.05 B 0.44 ± ± 0.16 < 0.05 Serum albumin (g %) A 3.25 ± 0.38 < ± 0.96 < 0.05 > 0.05 B 4.01 ± ± 0.25 < Body mass index (kg/m 2 ) A ± 2.6 < ± 3.18 > 0.05 > 0.05 B ± ± 3.26 < 0.05 Cardiovascular morbidity (%) A 0 > < 0.05 > 0.05 A = Baseline; B = After 6 months B < 0.01 Thus, the observations made in this study show that a substantial number of patients of ESRD had elevated levels of hs-crp. High levels of hs-crp were associated with poor clinical outcome in these patients due to interplay of a number of mechanisms including low haemoglobin, hypo-responsiveness to erythropoietin therapy, poor nutritional status, low albumin levels, greatly increased risk of cardiovascular disease and frequent and early need of haemodialysis. Discussion Despite improvement in dialysis technology over the past decade, mortality and morbidity in ESRD remains high 1. Recent evidence points to chronic inflammation as a major contributor to this mortality and morbidity 2. Traditional risk factors alone cannot explain the unacceptable high prevalence and incidence of cardiovascular disease in this population. Inflammation and other non-traditional risk factors are likely to contribute 9. Several factors have been implicated as potential causes of inflammation. These Among the several inflammatory biomarkers used to assess inflammation, hs-crp has attracted the most interest 11. hs-crp is 5-10-folds higher in haemodialysis patients than in healthy controls, and is multifactorial in origin 12. It has been a prominent product of the inflammatory response syndrome and a marker of overall and cardiovascular mortality in the general population and in ESRD patients 2. Raised levels of hs- CRP and other cytokines have been linked to anaemia leading to poor outcome in these patients 4. Proinflammatory cytokines and hs-crp are an important cause of lack of response to recombinant human erythropoietin therapy. The process of inflammation evidenced by elevated hs-crp levels also causes loss of muscle mass and changes in plasma composition leading to poor nutritional outcomes in ESRD population 13. In view of the increasing interest in the role of hs-crp as the most important marker of inflammation, this study was planned to see its prognostic significance in the patients of ESRD. 20 Journal, Indian Academy of Clinical Medicine Vol. 10, No. 1 & 2 January-June, 2009

4 The haemopoietic response to inflammation includes anaemia secondary to reduced erythropoiesis 4. This has been attributed to the inhibition of erythropoietin secretion by pro-inflammatory cytokines 14. Inflammation can also induce a functional iron deficiency, as cytokines can inhibit the delivery of iron from the reticuloendothelial cells to haemopoietic cells 15. Also, patients with high hs-crp levels showed poorer response to erythropoietin therapy meaning that the patients had low rise in haemoglobin (Hb) for same doses of EPO. It has been reported that the dose of EPO required for maintaining a certain Hb level in dialysis patients may be increased by 30-70% in those individuals who have high hs-crp levels as compared to those having lower values 16. The decreased survival reported in dialysis patients with markers of inflammation like hs-crp is probably related to association between inflammation and cardiovascular risk. The higher incidence of CVD in group II patients signify a strong correlation between cardiovascular disease and inflammation in ESRD 2. There are several ways in which inflammation can promote vascular injury, i.e., through alterations in lipoprotein structure and function, changes in the composition of plasma proteins, alterations in the vascular endothelium, and changes in the expression of specific ligands on the surfaces of platelets, neutrophils, and mononuclear cells 17. hs-crp levels correlated inversely with serum albumin (r = , p < 0.01). Albumin, like other nutritional markers, such as pre-albumin and transferrin, is a negative acute phase protein 18. The synthesis of these proteins decreases during inflammation, as does their serum concentrations, changes that are entirely independent of nutritional status 19. These results indicate that elevated serum markers of inflammation are associated with a poor nutritional outcome in ESRD patients resulting in increased morbidity and mortality. There was a linear relationship between hs-crp and clinical events leading to haemodialysis in this study, suggesting that inflammation influences the clinical outcome in these patients. Further, hs-crp levels were predictive of poor clinical outcome and early need for haemodialysis. The observations made in this study show that inflammation is a common feature in ESRD and is associated with an increased risk of morbidity and mortality. Raised levels of hs-crp were closely associated with poor outcomes due to interplay of a number of mechanisms including lower haemoglobin, poor response to erythropoietin on follow-up, high incidence of cardiovascular disease, poor nutritional outcomes as suggested by low serum albumin, and lower body mass index, as well as frequent and early hospitalisation for haemodialysis. Therefore, hs-crp should be included in the routine laboratory work-up for risk evaluation and stratification in ESRD. References 1. Hakim RM, Lazarus JM. Initiation of dialysis. J Am Soc Nephrol 1995; 6: Menon V, Wang X, Greene T et al. Relationship between C- reactive protein, albumin and cardiovascular disease in patients with chronic kidney disease. Am J Kidney Dis 2003; 42: Lowrie EG, Lew NL. Death risk in haemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 1990; 15: Barany P. Inflammation, serum C-reactive protein and erythropoietin resistance. Nephrol Dial Transplant 2001; 16: Pepys MB, Hirschfield GM. C-reactive protein: A critical update. J Clin Invest 2003; 111: Tsirpanlis G. The pattern of inflammation and a potential new clinical meaning and usefulness of C-reactive protein in end-stage renal failure patients. Kidney Blood Press Res 2005; 28: Ortega O, Rodriguez I, Gallar P et al. Vigil significance of high C-reactive protein levels in pre-dialysis patients. Nephrol Dial Transplant 2002; 17 (6): Herzig KA, Purdie DM, Cheng W. Is C-reactive protein a useful predictor of outcome in peritoneal dialysis patients? J Am Soc Nephrol 2001; 12: Stenvinkel P, Lindholm B. C-reactive protein in end-stage renal disease: are there reasons to measure it? Blood Purif 2005; 23: Kaysen GA. Microinflammatory state in uraemia: causes and potential consequences. J Am Soc Nephrol 2001; 12: Stenvinkel P, Lindholm B. C-reactive protein in end-stage renal disease: Are there reasons to measure it? Blood Purif 2005; 23: Wanner C, Metzger T. C-reactive protein a marker for allcause and cardiovascular mortality in haemodialysis Journal, Indian Academy of Clinical Medicine Vol. 10, No. 1 & 2 January-June,

5 patients. Nephrol Dial Transplant 2002; 17 (Suppl 8): Utaka S, Avesani CM, Draibe SA et al. Inflammation is associated with increased energy expenditure in patients with chronic kidney disease. Am J Clin Nutr 2005; 82 (4): Jelkmann W. Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res 1998; 18: Barany P. Inflammation, serum C-reactive protein and erythropoietin resistance. Nephrol Dial Transplant 2001; 16: Kaysen GA. Microinflammatory state in uraemia: causes and potential consequences. J Am Soc Nephrol 2001; 12: Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: Moshage HJ, Janssen JAM, Franssen JH et al. Study of the molecular mechanism of decreased liver synthesis of albumin and inflammation. J Clin Invest 1987; 79: Ritchie RF, Palomaki GE, Neveux LM et al. Reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: a practical, simple and clinically relevant approach in a large cohort. J Clin Lab Anal 1999; 13: Journal, Indian Academy of Clinical Medicine Vol. 10, No. 1 & 2 January-June, 2009