LCD L37561: Cystatin C Measurement

History/Background and/or General Information

Cystatin C is a low molecular weight protein produced by all nucleated cells in the body at a constant rate. Cystatin C is freely filtered by the renal glomerulus, completely reabsorbed by the proximal tubule, and then metabolized by the proximal tubule. It has been proposed and investigated as an improved marker of renal function and as a potential alternative to serum creatinine based estimated glomerular filtration rate (e GFR), as well as a biomarker for predicting cardiovascular risk.

Clinical assessment of kidney function is part of routine medical care for adults. GFR is the best overall index of kidney function. Normal GFR varies according to age, sex, and body size, and declines with age. Routinely, GFR is estimated from prediction equations which are based on endogenous serum markers like creatinine in addition to demographic variables such as age, sex and race. The National Kidney Foundation recommends using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation (2009) to estimate GFR.

Cystatin C is considered to be a potential alternative to serum creatinine for estimating GFR. GFR can be estimated (eGFR) from serum cystatin C utilizing an equation which includes the age and sex of the patient. Cystatin C eGFR may have advantages over creatinine eGFR in certain patient groups in whom muscle mass is abnormally high or low (e.g., individuals who are very elderly, malnourished, or have quadriplegia). Serum creatinine levels may also be influenced by diet (e.g., vegetarian or high protein diets) and medications that block distal tubule secretion of creatinine. Blood levels of cystatin C also equilibrate more quickly than creatinine. Therefore, serum cystatin C may be more accurate than serum creatinine when kidney function is rapidly changing (for example amongst hospitalized individuals).

Cystatin C levels have been reported to be abnormally elevated or decreased in some medical conditions (e.g., HIV disease and thyroid disease) and by some medications (e.g., corticosteroids). In clinical situations where confirmation of the eGFR by serum cystatin C is warranted, equations that combine serum cystatin C and serum creatinine provide a more precise eGFR than equations using serum cystatin C alone.

Estimation of GFR from serum creatinine remains the clinical standard worldwide.

Covered Indications

Cystatin C testing will be considered medically reasonable and necessary when all of the following are met:

in adults with eGFR creat 45–59 ml/min/1.73 m 2 (CKD stage 3A mildly to moderately decreased GFR) who do not have markers of kidney damage; and

if confirmation is warranted (i.e., when GFR estimates based on serum creatinine are thought to be inaccurate) (e.g., muscle mass is abnormally high or low, dietary intake, medications that block distal tubule secretion of creatinine); and

if confirmation is warranted (i.e., when decisions depend on a more accurate knowledge of the GFR, such as confirming a diagnosis of chronic kidney disease (CKD), determining eligibility for kidney donation, or adjusting the dosage of toxic drugs that are excreted by the kidneys).

Limitations

The following are considered not reasonable and necessary and therefore will be denied:

Measurement of cystatin C to assess cardiovascular risk is considered investigational in the risk assessment and management of cardiovascular disease. Cystatin C is not covered according to Title XVIII of the Social Security Act, Section 1861(xx)(1). Therefore, cystatin C measurement is considered not medically reasonable and necessary.

• Based on the Kidney Disease Outcomes Quality Initiative (KDOQI) US Commentary on the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation and Management of CKD, cystatin C testing is considered not medically reasonable and necessary for patients with following stages of CKD:

• Stage 1 Kidney damage with normal or elevated GFR > 90 ml/min/1.73 m 2

• Stage 2 Kidney damage with mild decrease in GFR 60-89 ml/min/1.73 m 2

• Stage 3B Moderately to severely decreased GFR 30-44 ml/min/1.73 m 2

• Stage 4 Severely decreased GFR 15-29 ml/min/1.73 m 2

• Stage 5 Kidney Failure GFR 2

Repetitive use of cystatin C testing without documented evidence supporting the medical necessity would not be expected.

As published in the CMS IOM Publication 100-08, Medicare Program Integrity Manual , Chapter 13, Section 13.5.4, an item or service may be covered by a contractor LCD if it is reasonable and necessary under the Social Security Act Section 1862 (a)(1)(A). Contractors shall determine and describe the circumstances under which the item or service is considered reasonable and necessary.

Evidence-based clinical guidelines

KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease

“The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD) serves to update the 2002 KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification following a decade of focused research and clinical practice in CKD. The document aims to provide state-of-the-art guidance on the evaluation, management and treatment for all patients with CKD. Specifically, the guideline retains the definition of CKD but presents an enhanced classification framework for CKD; elaborates on the identification and prognosis of CKD; discusses the management of progression and complications of CKD; and expands on the continuum of CKD care: timing of specialist referral, ongoing management of people with progressive CKD, timing of the initiation of dialysis, and finally the implementation of a treatment program which includes comprehensive conservative management. The development of the guideline followed an explicit process of evidence review and appraisal. Treatment approaches are addressed in each chapter and guideline recommendations are based on systematic reviews of relevant trials. Practical comments or statements which serve as educational purposes are ungraded, but included as important information for the readership. Appraisal of the quality of the evidence and the strength of recommendations followed the GRADE approach. Ongoing areas of controversies, limitations of the evidence, and international relevance are discussed and additional suggestions are provided for future research.”

The guideline recommends using serum creatinine and a GFR estimating equation for initial assessment of CKD. It suggests using additional tests (such as cystatin C or a clearance measurement) for confirmatory testing in specific circumstances when eGFR based on serum creatinine is less accurate. Confirmation of a decreased eGFR is warranted in specific circumstances where decisions depend on more accurate knowledge of the GFR, such as confirming a diagnosis of CKD, determining eligibility for kidney donation, or adjusting the dosage of toxic drugs that are excreted by the kidneys. It also suggests measuring cystatin C in adults with eGFR creat 45–59 ml/min/1.73 m 2 who do not have markers of kidney damage if confirmation of CKD is required. Another suggestion is measuring GFR using an exogenous filtration marker under circumstances where more accurate ascertainment of GFR will impact on treatment decisions.