**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 (eGFR), 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 gender 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 eGFRcreat 45-59 ml/min/1.73 m2 (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:

  1. 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. 

  2. 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 m2 
    * Stage 2 Kidney damage with mild decrease in GFR 60-89 ml/min/1.73 m2 
    * Stage 3B Moderately to severely decreased GFR 30-44 ml/min/1.73 m2 
    * Stage 4 Severely decreased GFR 15-29 ml/min/1.73 m2 
    * Stage 5 Kidney Failure GFR < 15 ml/min/1.73 m2

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 eGFRcreat 45-59 ml/min/1.73 m2 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.

**KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for the
Evaluation and Management of CKD**

"The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative
(NKF-KDOQI) guideline for evaluation, classification, and stratification of
chronic kidney disease (CKD) was published in 2002. The KDOQI guideline was
well accepted by the medical and public health communities, but concerns and
criticisms arose as new evidence became available since the publication of the
original guidelines. KDIGO (Kidney Disease: Improving Global Outcomes)
recently published an updated guideline to clarify the definition and
classification of CKD and to update recommendations for the evaluation and
management of individuals with CKD based on new evidence published since 2002.
The primary recommendations were to retain the current definition of CKD based
on decreased glomerular filtration rate or markers of kidney damage for 3
months or more and to include the cause of kidney disease and level of
albuminuria, as well as level of glomerular filtration rate, for CKD
classification. NKF-KDOQI convened a work group to write a commentary on the
KDIGO guideline in order to assist US practitioners in interpreting the KDIGO
guideline and determining its applicability within their own practices.
Overall, the commentary work group agreed with most of the recommendations
contained in the KDIGO guidelines, particularly the recommendations regarding
the definition and classification of CKD. However, there were some concerns
about incorporating the cause of disease into CKD classification, in addition
to certain recommendations for evaluation and management."

The guideline states estimation of GFR from serum creatinine remains the
clinical standard worldwide. It also recognizes the limitations of creatinine
and recommends additional confirmatory tests, such as measurement of cystatin
C or clearance, in situations when estimates of GFR from serum creatinine are
less accurate. For the purposes of estimation of measured GFR, the combination
of both markers (cystatin C and creatinine) provides a more precise estimate.
The guideline agrees that GFR estimation using cystatin C alone or in
combination with creatinine is useful as a confirmatory test of eGFR from
creatinine, and that it improves risk stratification.

**National Academy of Clinical Biochemistry Laboratory Medicine Practice
Guidelines: Emerging Biomarkers for Primary Prevention of Cardiovascular
Disease**

The guidelines state cystatin C may be a more powerful predictor of
cardiovascular events than eGFR calculation based on creatinine and recommends
additional research to determine if interventions based on cystatin C
measurements for risk stratification will provide added clinical benefit.
Also, the guidelines state cystatin C has been proposed and investigated as an
improved marker of renal function, a potential alternative to serum creatinine
based estimated GFR, and the results of a meta-analysis support serum cystatin
C as a promising, easily measured marker for detecting early kidney function
impairment.

**2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in
Asymptomatic Adults: Executive Summary**

The American College of Cardiology Foundation (ACCF) and the American Heart
Association (AHA) state "Global risk scores (such as the Framingham Risk Score
[FRS]) that use multiple traditional cardiovascular risk factors should be
obtained for risk assessment in all asymptomatic adults without a clinical
history of CHD. These scores are useful for combining individual risk factor
measurements into a single quantitative estimate of risk that can be used to
target preventive interventions."

Cystatin C is not referenced in the guideline. Therefore, there are no
recommendations for cystatin C testing for cardiovascular risk assessment.

**2013 ACC/AHA Cardiovascular Risk Assessment Guideline**

Members of the American College of Cardiology (ACC) and the American Heart
Association (AHA) Work Group proposed an initial list of novel risk markers
for inclusion in critical question 1 (CQ1), which was then prioritized during
several rounds of discussion. In selecting the final list, the Work Group gave
priority to factors that have engendered substantial discussion in the
scientific community and that could be reasonably considered as potentially
feasible for widespread population use by primary care providers in routine
clinical settings in the United States. In these deliberations, the Work Group
considered availability, cost, assay reliability, and risks of the test or
downstream testing. The final list of new risk markers to be evaluated
included several blood and urine biomarkers (hs-CRP [high-sensitivity
C-reactive protein], ApoB [Apolipoprotein B], creatinine [or eGFR], and
microalbuminuria), several measures of subclinical cardiovascular disease (CAC
[coronary artery calcium], CIMT [carotid intima-media thickness], and ABI
[ankle brachial index]), family history, and cardiorespiratory fitness. It was
noted that measurement of ApoB, albuminuria, GFR, or cardiorespiratory fitness
is of uncertain value. The contribution of ApoB, CKD, albuminuria, and
cardiorespiratory fitness to risk assessment for a first atherosclerotic
cardiovascular disease (ASCVD) event is uncertain at present.

Cystatin C is not referenced in the guideline. Therefore, there are no
recommendations for cystatin C testing for cardiovascular risk assessment.

The guideline from the National Kidney Foundation supports that estimation of
GFR from serum creatinine remains the clinical standard worldwide. However, it
acknowledges the limitations of serum creatinine and agrees with the KDIGO
2012 Clinical Practice Guideline suggestions for use of serum cystatin C as a
confirmatory test for eGFR when estimates of GFR from serum creatinine are
less accurate in adults with eGFRcreat 45-59 ml/min/1.73 m2 who do not have
markers of kidney damage and if confirmation is warranted.

Title XVIII of the Social Security Act, Section 1861(xx)(1) Cardiovascular
Screening Blood Test does not include Cystatin C measurement as a covered
service. The American College of Cardiology Foundation (ACCF), American
College of Cardiology (ACC) and the American Heart Association (AHA)
guidelines do not support serum cystatin C testing for cardiovascular risk
assessment.