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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2009  |  Volume : 20  |  Issue : 5  |  Page : 811-815
C-Reactive protein, a valuable predictive marker in chronic kidney disease


Department of Internal Medicine, Sri Ramachandra Medical College and Research Institute, Porur, Chennai, Tamil Nadu, India

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Date of Web Publication2-Sep-2009
 

   Abstract 

The aim of this study was to look for correlation between the markers for malnu­trition and inflammation, and atherosclerosis in pre-dialysis chronic kidney disease (CKD) patients. This observational study involved 100 pre dialysis patients (age 57 ± 12 years) from the out-patient and in-patient departments over a span of two years. Informed consent was obtained from all the study patients. Highly sensitive C-reactive protein (hsCRP) was assayed as a marker of chronic inflammation. Nutritional status was assessed using serum albumin and body mass index (BMI). Clinical and laboratory data were collected and a carotid doppler study was performed using duplex ultrasonography method to look for carotid artery stenosis. Renal function was assessed by cal­culating the estimated glomerular filtration rate (GFR) by the MDRD-2 formula. These data were later analyzed using descriptive statistics, Chi-square test and the students' t test. The mean GFR was 28.3 ± 16.4 mL/min/1.73m 2 . The mean value of CRP was 14.3 ± 11.4 mg /L. Sixty-seven percent of patients had elevated CRP (> 6 mg/L) levels. Patients with higher CRP levels showed lower mean serum albumin levels (3.2 ± 0.7 gm/dL) (P < 0.01). Only three patients had evidence of hemodynamically significant carotid disease (lumen diameter < 50%) with no statistical signifi­cance. Low serum albumin levels were associated with low hemoglobin levels (< 10 gm/dL), low GFR and presence of diabetes mellitus. Our results indicate that a high degree of inflammation and malnutrition exists in pre-dialysis patients as seen by high CRP values and low serum albumin levels. Synergism of these factors could contribute to atherosclerosis in CKD apart from the classic risk factors. To our knowledge, this is the first study, which has compared these markers of infla­mmation in pre-dialysis patients in developing countries.

How to cite this article:
Abraham G, Sundaram V, Sundaram V, Mathew M, Leslie N, Sathiah V. C-Reactive protein, a valuable predictive marker in chronic kidney disease. Saudi J Kidney Dis Transpl 2009;20:811-5

How to cite this URL:
Abraham G, Sundaram V, Sundaram V, Mathew M, Leslie N, Sathiah V. C-Reactive protein, a valuable predictive marker in chronic kidney disease. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2020 Oct 30];20:811-5. Available from: https://www.sjkdt.org/text.asp?2009/20/5/811/55367

   Introduction Top


The prevalence of chronic kidney disease (CKD) varies widely in Indian population and is found to be 785 per million population. [1] In­creasing evidence, accrued in the past decades, indicates that the adverse outcomes of CKD, such as kidney failure, cardiovascular disease (CVD) and premature death can be prevented or delayed. CVD has been found to be responsible for the majority of mortality and morbidity in this patient population and accounts for 40 to 50% of all deaths in end-stage renal disease (ESRD) patients. Also, mortality rates due to CVD are approximately 15-times higher in the ESRD population than in the general popu­lation. The Second National Healthy and Nutri­tion Examination Survey (NHANES II) showed that an estimated glomerular filtration rate (GFR) of less than 70 mL/min/1.73m 2 was associated with a 68% increase in the risk of death from any cause and a 51% increase in the risk of death from CVD. [2] In the Atherosclerosis Risk in Communities Study, an estimated GFR of 15­59 mL/min/1.73m 2 at baseline was associated with a 38% increase in the risk of CVD. [3] The higher prevalence of atherosclerotic lesions in uremic patients has been amply documented by autopsy studies. [4] These observations have vali­dated the hypothesis of accelerated atheroscle­rosis in renal failure. Recent studies have accu­mulated compelling evidence for a role of C­reactive protein (CRP) in improving risk pre­diction in this setting. [5] In the large Cardiovas­cular Health Study, renal insufficiency was independently associated with elevation of CRP, which may indicate an important pathway me­diating the increased cardiovascular risk in per­sons with kidney disease. [6] Elevated CRP levels are associated with an increase in the carotid intima-media area in CKD-pre-dialysis and dia­lysis patients. [7] In patients evaluated for chest pain, there was a significant correlation bet­ween severe coronary artery disease (CAD) and degree of carotid stenosis. [8]

Low serum albumin concentrations are highly associated with increased mortality risk in pa­tients on renal replacement therapy. [9] However, serum albumin is to a large extent influenced by factors other than malnutrition, and high con­centration of acute phase reactants such as CRP are correlated with low serum albumin in mal­nourished hemodialysis patients. [10] In malnutri­tion, increased oxidative stress in combination with chronic inflammation might lead to an in­creased risk of atherosclerosis. Therefore, the terminology malnutrition inflammation complex syndrome (MICS) or malnutrition inflammation and atherosclerosis (MIA) syndrome has been prepared to indicate the combination of these two conditions in these patients [11],[12] Chronic inflammation may be the missing link that actually ties protein energy malnutrition to mor­bidity and mortality in these individuals.


   Materials and Methods Top


This was an observational study conducted in a tertiary care center in South India and en­rolled both out-patients and in-patients belo­nging to different socio-economic strata. The inclusion criteria included the following:

  1. age greater than 18 years,
  2. CKD patients who were not initiated on dialysis,
  3. HsCRP value > 6 mg/L was taken as the cut off point for deciding the inflammatory status.


Patients with active infection, malignancy, on renal replacement therapy and renal transplant recipients were excluded from the study. Highly sensitive C-reactive protein (hs-CRP) was ana­lyzed using Nephelometry method (DADE BE­HRING) utilizing latex particles coated with CRP monoclonal antibodies. Serum albumin was measured by bromocresol blue method. The right and left carotid arteries were examined with a duplex scanner by the same trained radiologist. Internal carotid artery narrowing of hemodyna­mic significance (<_ 50%) was defined as an inter­nal carotid spectrum with a peak velocity below 1.25 m/sec and minimal spectral broadening du­ring the deceleration phase of systole. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula using the GFR cal­culator. Descriptive statistics such as mean and standard deviation were used for continuous variables.

Chi-square test has been applied to find any association between two categorical variables. Student's t-test has been used to find any sig­nificant difference between the normal and ab­normal groups of variables with respect to ave­rage values.


   Results Top


There were 100 patients with mean age of 57 ± 12 years. Fifty-five percent were men and the prevalence of diabetes mellitus was 59%. Mini­mum and maximum GFR were 4.17 and 73.21 mL/min/1.73m 2 with a mean GFR of 28.3 ± 16.4 mL/min/1.73m 2 . The mean BMI was 23.64 ± 4.7 kg/m 2 .

The mean value of HsCRP was 14.3 ± 11.4 mg/L (range 0.36 - 44.2 mg/L). Sixty-seven pa­tients showed a HsCRP level > 6 mg/L. There was no significant relationship between CRP levels and age, gender, diabetes mellitus, hyper­tension, nutritional data like BMI and hemo­globin levels. Patients with higher HsCRP levels showed lower serum albumin levels compared with patients with lower HsCRP levels (3.2 ± 0.7 vs 3.6 ± 0.5 g/dL, P < 0.01). There was also an inverse correlation between HsCRP levels and the GFR (P value < 0.05).

Lower serum albumin levels correlated with presence of diabetic mellitus, low hemoglobin levels (< 10 g/dL) and a low GFR. There was no correlation between serum albumin levels and hypertension or BMI.

Carotid Doppler was studied in 81 patients. Only three patients in this study had evidence of hemodynamically significant carotid disease defined as lumen diameter < 50%.


   Discussion Top


The high HsCRP levels in Indian CKD pa­tients indicate the high prevalence of inflamma­tion in non-dialysis patients. However, this was a cross sectional study and serial HsCRP levels were not monitored to assess the persistence of inflammation. Being a developing country, the great majority of patients cannot afford renal replacement therapy due to non-availability of governmental or health insurance support sys­tems. The percentage of CKD patients in stage­5 getting renal replacement therapy is very low in India. Diabetic nephropathy was the cause of CKD in 59% indicating its high prevalence in India. As in the dialysis population, high Hs­CRP levels in pre-dialysis patients predicts lo­wer serum albumin concentration. [13] Although the results of this study do not rule out the in­fluence of procedural variables on the infla­mmatory state, the number of patients with high HsCRP levels in our non-dialysis population was similar to the prevalence reported by Owen and Lowrie in a dialysis population. [14] This points to the fact that CKD patients, even in pre­dialysis stage, show signs of inflammation.

The average values of HsCRP were higher in this study (14.37 ± 11.4 mg/L) compared to ear­lier studies by Ortega et al (8.3 ± 14.2 mg/L) and Menon et al (2.2 mg/L) in pre-dialysis pa tients. [15],[16] There was no correlation of HsCRP level with diabetic status and hypertension as seen in previous reports. [15],[16] Stenvinkel et al re­ported that there was no association of HsCRP levels with gender and diabetic status in CKD patients. [7] He showed that the prevalence of mal­nutrition assessed by subjective global assess­ment (SGA) was significantly higher in patients with elevated HsCRP, but we did not observe any correlation between CRP and BMI in the present study. Menon et al had shown that Hs­CRP levels increased with age but such corre­lation was not seen in this study. [16] Ortega et al had observed that the mean value of hemo­globin was lower (P < 0.05) in patients with high HsCRP levels. However, it is surprising that there was no correlation between hemoglobin levels and HsCRP levels in the present study. There was a significant relationship between declining renal function and HsCRP levels (P < 0.05). However, this association was largely due to the high HsCRP levels in patients with Stage-5 CKD. This could probably be explained by the lower mean age of 52 ± 5 yrs in this group compared to the total mean age of 57 ± 12 yrs. There was also a low percentage (44%) of diabetics in Stage-5 CKD. Ortega et al and Menon et al found no correlation of CRP levels and GFR in their studies. In contrast to our fin­dings, Panichi et al noted higher HsCRP le-vels in patients with a creatinine clearance less than 20 mL/min (mean CRP 7.4 ± 6.3 mg/L) com­pared with those with a creatinine clearance greater than 20 mL/min (mean CRP 2.76 ± 4.35 mg/L). CRP levels in our non-dialysis patients correlated inversely with serum albumin (P value < 0.01) as in the dialysis population. Stenvinkel et al had established that patients with pre-ESRD CKD who were found to be malnourished, had markers consistent with the presence of inflammation. In this study, patients with high CRP levels showed lower serum al­bumin levels but without the presence of other markers of malnutrition like lower BMI. The mean serum albumin level in patients with high CRP (> 6 mg/L) was lower than in patients with low CRP values (3.2 ± 0.7 vs 3.6 ± 0.5 g/dL, P < 0.01). These results were similar to those ob­served by Ortega et al [15] (3.5 ± 0.4 vs 3.8 ± 4 g/dL, P < 0.05). Menon et al has shown that a high CRP level was associated with 0.07 g/dL lower mean albumin levels compared with pa­tients having low CRP values. [15] These data sup­port the hypothesis that protein energy malnu­trition and anorexia of uremia may be part of a malnutrition inflammation complex mediated by cytokines and this process begins in subjects with reduced GFR. However, serum albumin level may reflect the nutritional status and as a negative acute phase reactant. It is thus difficult to ascertain whether the relationship between CRP and albumin is caused by an association between inflammation and malnutrition or an association between one marker of inflammation and another.

Significant carotid disease (> 50 percent ste­nosis) was present only in three patients. Hence, its association with CRP and serum albumin could not be studied. We would need a larger sample population to ascertain this relationship. The drawbacks of this study are the relatively small sample size compared to earlier studies. Smoking, a risk factor for atherosclerosis was not studied as women formed a significant num­ber of patients and were non-smokers. Though carotid-intima media thickness is the earliest marker for atherosclerosis, we have assessed carotid stenosis as in the Framingham study. However, the smaller sample size with the majority being non-smokers in the study group, could also explain the inability to study the association between inflammation, malnutrition and carotid atherosclerosis.


   Conclusion Top


To our knowledge, this is the first study, which has compared these markers in non-dialysis CKD patients from a developing country. This study shows a high rate of inflammation in non dialysis patients as seen by high CRP levels. As in dialysis patients, high CRP levels in non­ dialysis patients are associated with lower se­rum albumin levels. It is possible that infla­mmatory processes precipitated by uremia per se could play a role in the development of mal­nutrition and atherosclerosis in patients with kidney disease.

 
   References Top

1.Abraham G, Moorthy AV, Aggarwal V. Chronic Kidney Disease: a silent epidemic in Indian subcontinent-strategies for management. J Ind Med Assoc 2006;104(12):689-91.  Back to cited text no. 1    
2.Muntner P, He J, Hamm L, Loria C, Whetton PK. Renal insufficiency and subsequent death from cardiovascular disease. J Am Soc Nephrol 2002;13:745-53.  Back to cited text no. 2    
3.Manjunath G, Tighromart H, Ibrahim H. Level of kidney function as a risk factor for cardio­vascular outcomes in the elders. Kidney Int 2003;63:1121-9.  Back to cited text no. 3    
4.Clyne N, Lins LE, Petrsson SK. Occurrence and significance of heart disease in Uraemia. Scan J Urol Nephrol 1986;20:307-11.  Back to cited text no. 4    
5.Arici M, Walls J. ESRD, atherosclerosis and cardiovascular mortality: is C-reactive protein the missing link? Kidney Int 2001;59:407-14.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Shilpak MG. Elevation of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation 2003;107:32-7.  Back to cited text no. 6    
7.Stenvinkel P, Heimburger O, Paultre F, et al. Association between malnutrition, inflammation and atherosclerosis is chronic renal failure. Kidney Int 1999;55:1899-911.  Back to cited text no. 7    
8.Kallikazaros I, Tsioufes C, Sides S, Stefandes C, Toutouzas P. Carotid artery disease as a marker for the presence of severe coronary artery disease in patients evaluated for chest pain. Stroke 1999;30:1002-7.  Back to cited text no. 8    
9.Lowrie EG. Death risk in haemodialysis patients. Am J Kidney Dis 1994;24:1010-8.  Back to cited text no. 9    
10.Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardio vascular risk and mortality in hemodialysis patients. Kidney Int 1999;55:648-58.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Kalantar-Zadeh K, Kopple JD. Relative contri­butions of nutritional and inflammation to clinical outcome in dialysis patients. Am J Kidney Dis 2001;38:1343-50.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Pecoits-Filho R. Malnutrition Inflammation: Atherosclerosis (MIA) syndrome Heart of the matter. Nephrol Dial Transplant 2002;17(Suppl 11):528.  Back to cited text no. 12    
13.Daniel Ski M, Izizler TA, McMonagle E, Kane JC, Pupin L, Morrow J. Linkage of hypoalbu­miunia, inflammation, and oxidative stress in patients receiving maintenance hemodialysis therapy. Am J Kidney Dis 2003;42(2):286-94.  Back to cited text no. 13    
14.Owen WF, Lowrie EG. C-reactive protein as a outcome predictor for maintenance hemo­dialysis patients. Kidney Int 1988;54:627-36.  Back to cited text no. 14    
15.Ortega O, Rodriguez I, Gallar P, et al. Signi­ficance of high C-reactive protein levels in predialysis patients. Nephrol Dial Transplant 2002;17:1105-9.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Menon V, Wang X, Green T, Beck GJ, Kusek JW, Marcovina SM. Relationship between C­reactive protein, albumen, and cardiovascular disease in patients with chronic kidney disease. Am J Kidney Dis 2003;42:44-52.  Back to cited text no. 16    

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Correspondence Address:
Georgi Abraham
Department of Internal Medicine, SRMC, Porur, Chennai, Tamil Nadu
India
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PMID: 19736479

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