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Comorbidities tests

 

This section has two parts:

  • Cardiovascular Disease and Chronic Kidney Disease (CKD)
  • Diabetes and CKD 

Cardiovascular Disease

There is a high prevalence of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Traditional risk factors for CVD derived from the Framingham Heart Study do not predict all deaths due to cardiovascular events or stroke1, and biomarkers can further help to identify patients at risk.

High sensitivity C-reactive protein
C-reactive protein (CRP) is an acute phase reactant that is elevated during infections and inflammation. High levels of CRP have been associated with increased mortality from CVD in the general population. CKD patients, especially those receiving dialysis have a microinflammatory state2, and have raised CRP levels. Increased CRP levels are associated with morbidity and mortality in CKD.

B-type natriuretic peptide (BNP) and N-terminal pro-BNP
BNP is a peptide released from ventricles in response to tension in the heart wall.  Levels are increased in patients with congestive heart failure and in acute coronary syndromes3. N-terminal pro-BNP levels are useful for risk stratification in patients with a variety of conditions including CKD4. Increased levels of both markers correlate with increased risk of death from cardiovascular complications in patients with CKD5.

Cardiac troponin T (cTnT)
Troponin T is a cardiospecific, highly sensitive marker of myocardial damage7. Myocardial cell injury leading to elevated serum cTnT concentrations can occur not only after myocardial infarction but also in congestive heart failure, cardiomyopathy, acute coronary syndromes and heart contusion6. Cardiac troponin T may also be used as a biomarker for the assessment of mortality in ESRD patients. Elevated cTnT levels can identify ESRD patients who have poor survival and are at a high risk of cardiac death7.
The use of a multi-biomarker panel including hsCRP, NT pro-BNP, and cTnT or cTnI has been shown to increase the ability to predict the relative risk for all cause mortality in ESRD patients, compared to each biomarker used separately8.

Hepcidin and pro-hepcidin
Hepcidin is an iron-regulatory peptide that is increased during inflammation9.  It is synthesized in the liver in response to increased iterleukin-6 (IL-6) production.  IL-6 levels are elevated during inflammation. This test allows the determination of the influence of inflammation and cytokines on the response to erythropoietic stimulating agents (ESAs).  Hepcidin blocks intestinal absorption of iron and the release of iron from macrophages.  High hepcidin levels are expected in ESRD patients and may be correlated with inability to utilize iron and to hypo-responsiveness to ESA therapy.

Asymmetric dimethylarginine (ADMA)
ADMA is an endogenous inhibitor of nitric oxide (NO) synthase.  High levels of ADMA can result in endothelial dysfunction and atherosclerosis.  ADMA levels are markedly increased in patients with CKD10, suggesting that it may play a role in atherosclerotic complications in these patients. ADMA levels correlate with left ventricular mass and with intima-media thickness of the carotid artery10.  Therefore, studies are needed to explore its potential as a biomarker of CVD progression in CKD patients.

Cystatin C
Serum Cystatin C measurements have been advocated as a more accurate measure of kidney function.  Recent studies in an elderly population with no evidence of CKD showed that elevated cystatin C (= 1.0 mg/L) can predict the risk of death, heart failure, stroke and myocardial infarction11.  In contrast, serum creatinine or GFR, calculated by the MDRD formula, could not predict death and only showed a weak correlation with CV death. Subjects with elevated cystatin C had a 4-fold increased risk of progression of CKD.

Diabetes

In most developed countries, diabetic nephropathy is the most common underlying cause of end stage renal disease (ESRD)12. Nephropathy is caused by long-term hyperglycaemia that induces a range of inflammatory processes within the blood vessel walls of the kidneys13.  Thirty to 40 percent of type 1 diabetics and 5–40% of type 2 diabetic patients develop nephropathy14. As the incidence of type 2 diabetes increases, the incidence of diabetic nephropathy is also expected to increase14. Loss of renal function loss is also accelerated by hypertension, a common co-morbidity with diabetes15. The first clinical evidence of diabetic nephropathy is microalbuminaria, which becomes apparent in 30–40% of the people with diabetes (types 1 and 2) after 20 years of disease. The increase in albuminuria is accompanied by a decrease in GFR over time16.
 
Albumin and Renal Function
The rate of renal function loss is in addition accelerated by hypertension, a common complication in patients with diabetes16.

Diabetic Biomarkers

Haemoglobin 1Ac (Hb1Ac)
Regular control of blood glucose levels decreases the potential complications of diabetes significantly17-20. HbA1c is one of the most important biomarkers to provide information about blood glucose. This biomarker provides information about the blood glucose levels over the previous eight to ten weeks.
In ESRD patients on dialysis, the use of HbA1c has not been validated specifically. This biomarker may under-represent glycemic control due to the decreased metabolism, anaemia, and a shorter life-span of the red blood cells. HbA1c may not an ideal indicator for glycemic control as suggested by some literature18-23. There is no clear HbA1c target established for patients on dialysis.
Another consideration is that the insulin doses needed during the transition from early chronic kidney disease (CKD) to end stage renal disease (ESRD) may change substantially. The NKF KDOQI guidelines advise to use newer insulin regimes and preparations with properties that are closer to normal physiology in patients on dialysis. In dialysis patients the following hypoglycaemic agents should be used with caution or not at all: Glyburide, Glipizide, Glimipride, Tolazamide and Chlorpropamide. This is because these sulfonylurea class drugs and their metabolites have a low clearance in patients on dialysis (NKF KDOQI).

Adiponectin
Adiponectin is an adipocytokine that is released by fat cells. Normal levels of adiponectin in human blood are 5–10 mg/dl24. There is an inverse relationship between the levels of adiponectin and the GFR in type 1 diabetes patients25. Several beneficial and protective actions have been attributed to adiponectin including anti-inflammatory, vasculoprotective, and anti-diabetic effects24. An anti-diabetic effect is also described in ESRD patients with diabetes who have decreased levels of adiponectin compared with non-diabetic individuals26.


References

  1. Stenvinkel P.  Inflammation in end-stage renal disease: the hidden enemy.  Nephrology (Carlton). 2006;11(1):36-41.
  2. Kaysen GA.  The microinflammatory state in uremia: causes and potential consequences.  J Am Soc Nephrol. 2001;12(7):1549-1557
  3. Jenberg T, Stridsberg M, Venge P, Lindahl B. N-Terminal Pro brain natriuretic peptide on admission for early risk stratification with chest pain and no ST-segment elevation. J Am Coll Cardiol 2002;40:437-445.
  4. Costello-Boerrigter LC, Burnett JC Jr. The prognostic value of N-terminal proB-type natriuretic peptide. Nat Clin Pract Cardiovasc Med. 2005;2(4):194-201
  5. Austin WJ, Bhalla V, Hernandez-Arce I, Isakson SR, Beede J, Clopton P, Maisel AS, Fitzgerald RL. Correlation and prognostic utility of B-type natriuretic Peptide and its amino-terminal fragment in patients with chronic kidney disease. Am J Clin Pathol. 2006 Oct;126(4):1-7.
  6. Ohman EM, Armstrong PW, Christenson RH, Granger CB, Katus HA, Hamm CW, O'Hanesian MA, Wagner GS, Kleiman NS, Harrell FE Jr, Califf RM, Topol EJ. Cardiac Troponin T Levels for Risk Stratification in Acute Myocardial Ischemia. N Engl J Med. 1996; 335:1333-1341.
  7. Khan NA, Hemmelgarn BR, Tonelli M, Thompson CR, Levin A. Prognostic value of troponin T and I among asymptomatic patients with end-stage renal disease: a meta-analysis. Circulation. 2005;112(20):3088-3096.
  8. Apple FS, Murakami MM, Pearce LA, Herzog CA. Multi-biomarker risk stratification of N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and cardiac troponin T and I in end-stage renal disease for all-cause death.  Clin Chem. 2004;50:2279-2285.
  9. Deicher R, Hörl WH. Hepcidin: a molecular link between inflammation and anaemia. Nephrol Dial Transplant 2004;19:521-524.
  10. Zoccali C, Mallamaci F, Tripepi G.  Asymmetric dimethylarginine (ADMA) as a cardiovascular risk factor in end-stage renal disease (ESRD).  Eur J Clin Pharmacol. 2006; 62 Suppl 13:131-135.
  11. Shlipak MG, Katz R, Sarnak MJ, Fried LF, Newman AB, Stehman-Breen C, Seliger SL, Kestenbaum B, Psaty B, Tracy RP, Siscovick DS. Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease. Ann Intern Med. 2006;145:237-246
  12. Candido, R., B. Fabris, and M. Cooper, Treatment for diabetic nephropathy-A review of the recent patent literature. IDrugs, 2002. 5(3): p. 237-65.
  13. Jerums, G., et al., Evolving concepts in advanced glycation, diabetic nephropathy, and diabetic vascular disease. Arch Biochem Biophys, 2003. 419(1): p. 55-62.
  14. Bell, D. and J. Alele, Dealing with diabetic nephropathy. Postgraduate Medicine, 1999. 105(2): p. 83-7.
  15. Phillips, C. and M. Molitch, The Relationship Between Glucose Control and the Development and Progression of Diabetic Nephropathy. Current Science, 2002. 2: p. 523-529.
  16. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anaemia in chronic kidney disease. Available at: http://www.kidney.org/professionals/kdoqi/guidelines_cvd/guide11.htm
    Accessed on: February 15, 2007.
  17. Group, T.D.C.a.C.T.R., The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine, 1993. 329: p. 977-986.
  18. Group, U.P.D.S.U., Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet, 1998. 352: p. 837-53.
  19. Group, U.P.D.S.U., Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet, 1998. 352: p. 854-865.
  20. Group, T.D.C.a.C.T.E.o.D.I.a.C.R., Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. New England Journal of Medicine, 2000. 342: p. 381-389.
  21. Oyibo, S., et al., Blood glucose overestimation in diabetic patients on continuous ambulatory peritoneal dialysis for end-stage renal disease. Diabetic Medicine, 2002. 19(8): p. 693-696.
  22. Joy, M., et al., Long-term glycemic control measurements in diabetic patients receiving hemodialysis. Am J Kidney Dis, 2002. 39(2): p. 297-307.
  23. Tzamaloukas, A., Interpreting glycosylated hemoglobin in diabetic patients on peritoneal dialysis. Adv Perit Dial, 1996. 12: p. 171-5.
  24. Guzik, T., D. Mangalat, and R. Korbut, Adipocytokines - Novel link between inflammation and vascular function? Journal of Physiology and Pharmacology, 2006. 57(4): p. 505-528.
  25. Schalkwijk, C., et al., Adiponectin Is Inversely Associated with Renal Function in Type 1 Diabetic Patients. 2006, Endocrine Soc.
  26. Karakitsos, D., et al., Adiponectin and Cardiovascular Remodeling in End-Stage Renal Disease and Co-Morbid Diabetes Mellitus. Am J Nephrol, 2006. 26(4): p. 340-347.