Elevated CRP Linked With CKD Risk in Rheumatoid Arthritis

Tight control of inflammation in RA may provide additional benefits for preventing the development of CKD.
Tight control of inflammation in RA may provide additional benefits for preventing the development of CKD.

Researchers from Okinawa, Japan have found that persistently high C-reactive protein (CRP) was a significant, independent risk factor for chronic kidney disease (CKD) in patients with rheumatoid arthritis (RA). The results are published in PLoS ONE.

The researchers noted that CKD is common in patients with RA2-6, and that several conditions may explain the association between the CKD and RA, including secondary amyloidosis, glomerulonephritis, or drug-related causes.7,8

“However, specific causes of CKD generally are not determined among most patients with RA. Thus, it is critically important to elucidate the risk factor for the incidence of CKD among them… [and] it seems to be clinically important to elucidate whether the degree of inflammation in short-term period may have an impact on renal outcome,” wrote Masako Kochi, from the University of the Ryukyus School of Medicine, in Nishihara, Okinawa, Japan, and the Yuuaikai Nanbu Hospital in Itoman, Okinawa, Japan and colleagues.

The researchers therefore decided to examine CRP, a marker of inflammation that is associated with RA disease activity, to see if there was an association between elevated CRP levels and CKD in patients with RA over a period of 6 months.

Using digital medical records from Tomishiro Central Hospital in Okinawa, Japan, the researchers retrospectively examined the relationship between CRP levels and CKD in 345 patients with RA (mean age 57.2 years, 85% women). They defined CKD as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, and/or positive dipstick testing for proteinuria for ≥3 months. High CRP was defined as >3.0 mg/L.

The researchers took 3 measurements of CRP over a 6 month period, and divided the participants into 3 groups: patients with no high CRP values (group 1), patients with high CRP values once or twice (group 2), or patients with persistently high CRP values (group 3).

During a median follow-up of 89 months, 14% of patients developed CKD, with breakdowns in each group as follows: group 1: 7%;  group 2: 14%; and group 3: 22% (P = .008, log-rank test). In a multivariate analysis that included classical risk factors for CKD, persistently high CRP was an independent predictor of CKD (hazard ratio, 3.00; 95% confidence interval, 1.23–8.53; P = .01).

High Yield Data Summary

  • Persistently elevated CRP (6 months) was found to be an independent risk factor for the development of CKD in RA 

The researchers noted that in previously conducted population-based studies, one measurement of CRP did not predict a risk of developing an eGFR <60 mL/min/1.73 m2.9,10 

The authors noted that this may be because “RA is a chronic inflammatory disease characterized by unpredictable fluctuations in disease activity, and CRP is an acute-phase reactant protein produced in many inflammatory conditions. Thus, measuring its level at a single time point may not be reflective of the true association between the persistently high CRP and incidence of CKD.”

The researchers also noted that several mechanisms may be involved in an association between inflammation and CKD.

1. A previously conducted study found a correlation between elevated CRP and blood pressure, glucose, lipids, and BMI in non-diabetics with CKD.  This may therefore indicate that the relationship between elevated CRP and risk for CKD may be confounded by these factors.

2. While toxic effects of the drugs needed to treat RA may be responsible for associations between high CRP and CKD, findings from this study showed that consistently high CRP levels predicted CKD after adjustment for these drugs. “Thus, persistent inflammation might have an independent role in the development of CKD,” the authors noted.

3. Elevated CRP in some patients may be related to the incidence of CKD defined as eGFR < 60 mL/min/1.73 m2, and/or positive dipstick testing for proteinuria due to a state of hyperfiltration.

“To the best of our knowledge, the present study is the first to provide evidence showing that persistent elevation of CRP for at least 6 months is a significant risk factor for the development of CKD in patients with RA from a retrospective cohort setting with 89-months follow-up period,” the authors wrote. 

Summary and Clinical Applicability

Researchers from Okinawa, Japan have found that persistently high C-reactive protein (CRP) was a significant risk factor for chronic kidney disease (CKD) in patients with rheumatoid arthritis (RA).

“Thus, tight control of inflammation in RA may provide additional benefits for preventing the development of CKD. This notion was supported by the finding that MTX, which have potential nephrotoxicity, remains as a protective factor rather than a risk factor for incidence of CKD even after adjustment with confounding factors,” the authors concluded.

Limitations and Disclosures

  • Dipstick testing was performed to test for proteinuria, but testing for albuminuria was not performed because measuring albuminuria was not reimbursed for these patients
  • Changes in medication use, RA disease activity, or control status of traditional risk factors were not taken into account
  • The causes of CKD were not evaluated in this study. Future studies are needed that include detailed clinical and pathological evaluation

The authors report no conflicts of interest to disclose.

Sources

1. Kochi M, Kohagura K, Shiohira Y, Iseki K, Ohya Y. Inflammation as a Risk of Developing Chronic Kidney Disease in Rheumatoid Arthritis. PLoS ONE. 2016; doi:10.1371/journal.pone.0160225.

2. Mustonen J, Helin H, Korpela M, Pasternack A. Rheumatoid arthritis and the kidneys. Duodecim. 1985;101(16):1549–56.

3. Boers M, Dijkmans BA, Breedveld FC, Camps JA, Chang PC, van Brummelen P, et al. Subclinical renal dysfunction in rheumatoid arthritis. Arthritis Rheum. 1990 Jan;33(1):95–101. doi:10.1002/art.1780330113.

4. Koseki Y, Terai C, Moriguchi M, Uesato M, Kamatani N. A prospective study of renal disease in patients with early rheumatoid arthritis. Ann Rheum Dis. 2001 Apr;60(4):327–31.

5. Karstila K, Korpela M, Sihvonen S, Mustonen J. Prognosis of clinical renal disease and incidence of new renal findings in patients with rheumatoid arthritis: follow-up of a population-based study. Clin Rheumatol. 2007 Dec;26(12):2089–95. doi: 10.1007/s10067-007-0625-y.

6. Karie S, Gandjbakhch F, Janus N, Launay-Vacher V, Rozenberg S, Mai Ba CU, et al. Kidney disease in RA patients: prevalence and implication on RA-related drugs management: the MATRIX study. Rheumatology (Oxford). 2008 Mar;47(3):350–4. doi: 10.1093/rheumatology/kem370.

7. Helin HJ, Korpela MM, Mustonen JT, Pasternack AI. Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis. Arthritis Rheum. 1995 Feb;38(2):242–7. doi:10.1002/art.1780380213.

8. Nakano M, Ueno M, Nishi S, Shimada H, Hasegawa H, Watanabe T, et al. Analysis of renal pathology and drug history in 158 Japanese patients with rheumatoid arthritis. Clin Nephrol. 1998 Sep;50(3):154–60.

9. Shankar A, Sun L, Klein BE, Lee KE, Muntner P, Nieto FJ, et al. Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population-based cohort study. Kidney Int. 2011 Dec;80(11):1231–8. doi:10.1038/ki.2011.283.

10. Hiramoto JS, Katz R, Peralta CA, Ix JH, Fried L, Cushman M, et al. Inflammation and coagulation markers and kidney function decline: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis. 2012 Aug;60(2):225–32. doi:10.1053/j.ajkd.2012.02.335.

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