Chronic kidney disease (CKD) is a major public health problem that is increasing in incidence and prevalence and is associated with poor outcomes and high costs.1 Six of every 10 Americans will develop kidney disease.2 CKD now affects more than 11% of the U.S. population and is a major contributor to morbidity and mortality.3 In 2013, 26 million U.S. adults had advanced CKD, and Medicare expenses for CKD in stages 2 through 4 exceeded $48 billion.1,3
Long-term adverse outcomes associated with CKD include impaired kidney function (and associated complications), cardiovascular disease (CVD), kidney failure and death.4 Given the significant incidence and costs, it is alarming to learn that less than half of Americans with CKD are aware they have damaged kidneys or decreased kidney function.5 It is time for patients and providers alike to develop a heightened awareness of CKD. Early detection and management of CKD can often delay progression.
Classification of CKD
Guidelines for the definition and classification of CKD were first published in 2002 by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI). The document was endorsed by a panel of international experts, Kidney Disease: Improving Global Outcomes (KDIGO), in 2004. The NKF-KDOQI believed the definition and classification of CKD should reflect patient prognosis and that an analysis of outcomes would provide answers to key questions about the progression of the disease. This framework promoted increased attention to CKD in clinical practice, research and public health while generating further research to document the efficacy of the guidelines.6-8
A decade after publication of the first definition and classification of CKD, KDIGO released an update.9 The new guidelines apply to all patients with CKD who are not receiving renal replacement therapy (kidney transplant or dialysis). These guidelines seek to provide comprehensive guidance for the CKD pathway, from early identification and diagnosis through initiation of renal replacement therapy for end-stage renal disease (ESRD) or end-of-life care.9
Brief Review of GFR
The kidney performs multiple excretory and endocrine functions, the most important being the filtration of wastes. The filtering units of the kidney are the glomeruli, which filter approximately 180 liters per day (125 mL/min) of plasma. A normal value for glomerular filtration rate (GFR) (depending on age, sex and body size) is approximately 130 mL/min/1.73 m2 for men and 120 mL/min/1.73 m² for women. Considerable variation in GFR exists, even among healthy patients. Causes of variation include time of day, protein intake, type of protein (animal vs. vegetable, essential vs. nonessential amino acids) and physical activity. Pregnancy and antihypertensive agents can also affect GFR.10,11
All GFR formulas use similar criteria for calculation: age, sex, race, weight and serum creatinine. Although it is not an ideal filtration marker, creatinine level is the most commonly used test for estimating GFR. Creatinine is easy to measure and assays are inexpensive and widely available. Creatinine is standardized and can be measured in serum, plasma or urine. The most commonly used equations are the Cockcroft-Gault (C-G) and the Modification of Diet in Renal Disease (MDRD).10-12
The central role of GFR reflects a consensus that GFR is the best overall measurement of kidney function and the most easily understood by providers and patients. Using GFR, public health campaigns focus on messages such as "Know Your Number" or "Save Your GFR" as a strategy analogous to those used for hypertension or hyperlipidemia. National and international organizations recommend that clinicians use estimating equations for GFR to assess kidney function and that clinical laboratories report the estimated GFR whenever serum creatinine (Scr) is measured.4,7,8
Definition and Classification
In 2002, the NKF-KDOQI defined CKD as a GFR of < 60 mL/min/1.73 m² or kidney damage for 3 or more months and/or albuminuria. Albuminuria, defined as more than 30 mg of urinary albumin per gram of urinary creatinine, was based on a random urine test, with first-morning voided urine being the gold standard. These guidelines provided both a staging system for CKD based on GFR and stage-specific recommendations for evaluation and management. As GFR level falls and CKD stage increases, so does the range of symptoms and complications, including hypertension, anemia, malnutrition, bone disease, and neuropathy. Evidence has demonstrated an increased risk for CVD and mortality as GFR falls. The 2002 KDOQI definition raised concerns about overdiagnosis of CKD, methods and threshold of GFR measurement, and whether risk was related to CKD stage or an unknown factor.7,8
In January 2013, KDIGO published new guidelines addressing many of the stated concerns and updating research with studies conducted over the prior 10 years.9 The document defines CKD as abnormalities of kidney structure or function present for more than 3 months with implications for health. It specifies CKD criteria for albuminuria (albumin excretion rate ≥ 30 mg/g; albumin/creatinine ratio ≥ 30m g/g on a spot urine), urinary sediment abnormalities, electrolyte and other abnormalities due to tubular disorders, histologic abnormalities, structural abnormalities noted in imaging detection, history of kidney transplantation and decreased GFR for longer than 3 months.9
KDIGO further recommends that CKD classification be based on cause, GFR category, severity and albuminuria category (Figure 1). Identification of cause is emphasized because of its fundamental importance in predicting outcome and guiding choice of cause-specific treatments. Severity is expressed by level of GFR and albuminuria. Severity is linked to risks for adverse outcomes, including death and end-stage kidney disease.
In the new classification, the previous five-stage GFR categories are retained but with subdivisions of Stage 3 (30 mL/min per 1.73 m2 to 59 mL/min per 1.73 m²) into categories G3a (45 mL/min per 1.73 m2 to 59 mL/min per 1.73 m²) and G3b (30 mL/min per 1.73 m2 to 44 mL/min per 1.73 m²). This change, outlined in Figure 2, was driven by data supporting different outcomes and risk profiles in these categories. In addition to the GFR categories, three albuminuria categories were added (Figure 3).9
GFR Measurement Equations
Prior to 2009, the most commonly used methods to estimate GFR were the C-G and the MDRD Study equations. The C-G formula was developed in 1973 and estimated creatinine by correcting for body size. Studies revealed that the C-G systematically overestimates GFR because it was developed to estimate creatinine clearance and not GFR. Furthermore, because of the inclusion of weight as a measure of muscle mass, it overestimates creatinine clearance in patients who are edematous, overweight or obese.12,13
The more recently developed MDRD Study equation uses a four-variable equation adjusted for body surface area and based on SCr, age, sex and race. The MDRD Study equation was tested in a predominantly white population with CKD who were neither diabetics nor kidney transplant recipients. 12-16
These two estimating equations do not account for all determinants of SCr. They do not account for alterations in muscle mass among patients with muscle disorders, amputations, very low-protein diets or a history of body building. Furthermore, the formulas are not accurate for patients with rapidly changing kidney function such as those with acute kidney injury (AKI).17,18 The typical CKD patient is a nonwhite patient with diabetes, and a new formula was needed for this population.
Click to view larger graphic.
To address some of the limitations of the current GFR estimation equations, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was developed in 2009. The new KDIGO guidelines recommend CKD-EPI for estimating GFR in adults.9
Systematic review supports the strength of this recommendation. The CKD-EPI equation has less bias than the MDRD Study equation.15,17,18 Most national and international studies show that the CKD-EPI equation is more accurate than the MDRD Study equation, especially at a higher GFR.9,18-20 However, few laboratories report CKD-EPI at this time. NPs and PAs should be aware of what formula is being used for calculation and the associated limitations.
Guidelines for Management
The KDIGO document provides guidance for the management and treatment of CKD. The recommendations include 110 items covering issues from prevention of CKD progression to management of complications of CKD. KDIGO provides key recommendations about CKD monitoring frequency, blood pressure control, proteinuria reduction, lifestyle intervention, diabetes control and cardiovascular disease.9,21 The document is available at http://kdigo.org/home/guidelines/.
Patients at risk for CKD or who have CKD should be assessed at least annually. The frequency of GFR measurement and urine albumin/creatinine ratio monitoring depends on CKD severity.
Patients with expected progression of CKD due to CKD cause, GFR level, albuminuria level, AKI, age, sex, race, ethnicity, elevated blood pressure, hyperglycemia, dyslipidemia, smoking, obesity, history of cardiovascular disease, or ongoing exposure to nephrotoxic agents require more frequent monitoring.
Studies have found that small fluctuations in GFR are common and do not necessarily indicate progression. KDIGO defines progression as a GFR increase of 25% or more.9
Control of blood pressure and reduction of proteinuria are critical in preventing CKD progression. Evidence has consistently supported a reduction of proteinuria by interrupting the rennin-angiotensin-aldosterone system. This slows progression of both diabetic and nondiabetic nephropathy. Lowering blood pressure also slows CKD progression, breaking a potentially vicious feedback loop between hypertension and CKD.9
Lifestyle interventions also play an important role in reducing proteinuria and slowing CKD progression.9 Specific lifestyle strategies are: reducing sodium intake to less than 2 grams per day; achieving a healthy body mass index of 20 kg/m2 to 25 kg/m²; smoking cessation; and cardiovascular exercise performed 30 minutes five times per week.
Recommendations for diabetes management are extensively addressed in the new guidelines.
KDIGO emphasizes that good diabetes control, signified by a hemoglobin A1c level of 7% or less, is the the goal for each patient at risk for or in the early stages of chronic kidney disease.9
The recommendation regarding ischemic heart disease among patients with CKD is worth mentioning. Patients with CKD are more likely to have a cardiovascular event than to progress to ESRD. Compared to patients without CKD, they have a worse prognosis and higher mortality rates after an acute myocardial infarction and are at higher risk for recurrent myocardial infarction, heart failure and sudden cardiac death.9 The guidelines encourage known protective cardiovascular treatments for patients with CKD, but they also state that brain natriuretic peptide testing for heart disease is invalid in patients with a GFR < 60mL/min/1.732.9
Future Challenges & Endeavors
The convergence of basic science investigations and modern clinical epidemiologic techniques has ushered in an era of discovery and novel biomarkers for kidney disease. These biomarkers - beta-trace protein, neutrophil gelatinase-associated lipocalin, urinary liver-type fatty acid binding protein, asymmetric dimethylarginine, urinary kidney injury molecule 1 and fibroblast growth factor 23 - are still in development but are promising.
To be useful in clinical practice, these new biomarkers of CKD progression will have to prove superior to the prognostic ability of estimated GFR and albuminuria. They will need to improve precision, bias and the prognostic ability of creatinine levels. Studies from the National Institute of Heath CKD Biomarkers Consortium and other investigators are under way to identify and validate these novel biomarkers.22
A Final Thought
Some authors consider us at a crossroads in the treatment of CKD.23After 50 years of providing dialysis to patients in ESRD and despite the development of care improvements and quality outcomes, the survival, quality of life and mortality of patients with ESRD has not changed and is suboptimal. Ambrose Tsang, a nephrologist practicing in Downey, Calif., challenges nephrology practitioners with the question: "What can we do to improve the care of ESRD patients?" The answer, in large part, lies in preventing ESRD by reaching patients before they reach end stage.
Primary care providers are often a patient's best defense against advancing kidney disease. Without help from our primary care colleagues, those of us in nephrology are just trying to swim upstream without a paddle. We ask that you reach out to us for any help or questions. We need you just as much as you need us.
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13. Tangri N, et al. A predictive model for progression of chronic kidney disease to kidney failure. JAMA. 2011;305(15): 1553-1559.
14. McFarlane SI, et al. Comparison of CKD epidemiology collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) study equations: prevalence of and risk factors for diabetes mellitus in CKD in the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis. 2011;57(3 suppl 2):S24-S31.
15. Matsuhita K, et al. Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate. JAMA. 2012;307(18):1941-1951.
16. Chen S. Retooling the creatinine clearance equation to estimate kinetic GFR when the plasma creatinine is changing acutely. J Am Soc Nephrol. 2013;24(6):877-888.
17. Stevens LA, et al. Comparative performance of the CKD epidemiology collaboration (CKD-EPI) and the modification of diet in renal disease (MDRD) Study equations for estimating GFR levels above 60 mL/min/1.73 m2. Am J Kidney Dis. 2010;56(3):486-495.
18. Tent H, et al. Performance of MDRD study and CKD-EPI equations for long term follow-up of nondiabetic patients with chronic kidney disease. Nephrol Dial Transplant. 2012;27(Suppl 3): iii89-iii95.
19. Schold JD, et al. Implications of the CKD-EPI GFR estimation equation in clinical practice. Clin J Am Soc Nephrol. 2011;6(3):497-504.
20. Silveiro SP, et al. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation pronouncedly underestimates glomerular filtration rate in type 2 diabetes. Diabetes Care. 2011;34(11):2353-2355.
21. Levey AS, et al. Definition and classification of kidney diseases. Am J Kidney Dis. 2013;61(5):686-688.
22. Coresh J. A decade after the KDOQI CKD Guidelines: impact on research. Am J Kidney Dis. 2012;60(5):701-704.
23. Parker TF 3rd, et al. Dialysis at a crossroads-Part II: a call for action. Clin J Am Soc Nephrol. 2012;7(6):1026-1032.
Janett Delacruz is a nurse practitioner who practices with Ambrose Tsang, MD, a nephrologist in Downey, Calif. She has completed a disclosure statement and reports no relationships related to this article.