LABORATORIO DE URGENCIAS

 

Uses of GFR and Albuminuria Level in Acute and Chronic Kidney Disease

 

     Andrew S. Levey, M.D., Morgan E. Grams, M.D., Ph.D., M.H.S., and Lesley A. Inker, M.D.

 

                                                                           N Engl J Med 2022; 386:2120-2128
                                                                                               Review Article

 

Kidney disease is common in adults, and testing for kidney disease is part of routine clinical practice for patients with acute or chronic illness. The initial evaluation includes determination of the glomerular filtration rate (GFR), estimated on the basis of the serum creatinine level (eGFRcr), and the level of albuminuria, assessed on the basis of the urinary albumin-to-creatinine ratio. These tests are inexpensive, are widely available in clinical laboratories, and enable early detection of most kidney diseases. Calculation of the eGFR from the serum cystatin C level alone or with the serum creatinine level (eGFRcys and eGFRcr-cys, respectively) is a recommended confirmatory test but is less widely available, particularly in countries outside the United States and western Europe. Rigorous evaluation of GFR and albuminuria has enabled advances in clinical practice, research, and public health, but greater use of these measures is needed to improve health outcomes related to kidney disease.

It has been 20 years since the first clinical practice guideline on kidney disease recommended the use of the GFR and albuminuria for defining and classifying kidney disease.¹ In this review, we briefly discuss the conceptual model and clinical approach to detection, evaluation, and management of acute kidney disease (AKD) and chronic kidney disease (CKD), using internationally recommended nomenclature.^2,3 
We then focus on advances in clinical evaluation of the GFR and albuminuria and application of these measures as criteria for the definitions of AKD and CKD, risk factors for cardiovascular disease, eligibility criteria and end points for clinical trials of kidney disease progression, and risk prediction instruments for clinical practice

CLINICAL APPROACH TO KIDNEY DISEASE

Current guidelines define kidney disease as heterogeneous disorders characterized by abnormalities in the function or structure of the kidney, with implications for health
Functional abnormalities are related to a decreased GFR, whereas structural abnormalities are inferred from markers of kidney damage, including increased albuminuria and abnormalities in the urine sediment and imaging.
New biomarkers of kidney function and structure are under investigation.⁷ AKD and CKD are differentiated by their duration: less than 3 months for AKD and 3 months or longer for CKD. Acute kidney injury (AKI) is defined as a subset of AKD, with an onset within 7 days before presentation. AKD with or without AKI can be superimposed on preexisting CKD.⁸ Kidney disease is classified according to the cause and severity (stages) of GFR and albuminuria (known as cause–GFR–albuminuria classification, or CGA staging) because of the importance of each of these factors in prognosis and treatment.

There are numerous risk factors for and causes of AKD and CKD.  Older age, diabetes, hypertension, and obesity are among the most common risk factors. Regardless of the cause of disease, adverse outcomes include progression to kidney failure, complications in other organs and tissues, and death. Kidney failure generally causes symptoms and may require short-term or long-term kidney-replacement therapy (dialysis or transplantation). Kidney failure requiring long-term kidney-replacement therapy is also known as end-stage kidney disease. Complications may involve virtually all organs and tissues, but causal mechanisms are incompletely understood. Kidney failure and complications associated with kidney disease (especially cardiovascular disease [CVD]) contribute to decreased quality of life, higher costs of care, and increased mortality, especially among older adults.

The general clinical approach to AKD (with or without AKI) and CKD consists of six steps:
* First, recognition of patients who are at increased risk for kidney disease
* Second, testing of patients at increased risk, even in the absence of symptoms
* Third, detection with the use of guideline-recommended criteria
* Fourth, evaluation of cause and stages (cause–GFR–albuminuria classification)
* Fifth, assessment of prognosis (risk) for kidney disease progression and complications
* Sixth, implementation of risk-based therapy, including cause-specific therapy and stage-based nonspecific therapy.
Treatment is designed to slow progression and reduce complications for patients in whom the anticipated benefits of treatment (risk reduction) outweigh the anticipated harms.

CLINICAL EVALUATION OF GRF AND ALBUMINURIA

GFR and albuminuria reflect the glomerular contributions to the excretory function of the kidneys and are the most well-characterized measures of kidney disease. GFR, the product of the number of nephrons and the average single-nephron GFR, is generally considered the best overall index of kidney function in health and disease.⁹ 
The nephron number declines with age and kidney disease.^10,11 Physiologically, the consequent decline in GFR can be counteracted by an increase in single-nephron GFR (single-nephron hyperfiltration), which can blunt the decline in the overall GFR, but over time, this may result in hemodynamic injury to the remaining nephrons and accelerated progression of kidney disease.

The true GFR cannot be measured directly in humans. GFR can be assessed from the clearance or plasma (or serum) concentrations of filtration markers (low-molecular-weight substances that are eliminated primarily by glomerular filtration). For evaluation of the GFR, current guidelines recommend using GFR-estimating equations, with eGFRcr as the initial test, and confirmation with eGFRcys, eGFRcr-cys, or clearance measurements, as appropriate for the clinical setting⁵ GFR can be assessed more accurately with the use of estimating equations than by the concentration of the filtration marker alone. 
The equations developed by the Chronic Kidney Disease Epidemiology Collaboration are recommended for use in North America, Europe, and Australia. Alternative equations for eGFRcr are used in some regions of Asia; there are limited studies from South America and Africa.¹² Furthermore, recent recommendations encourage the use of serum cystatin C levels in estimating the GFR because cystatin C is not affected by race or world region and appears to enable a more accurate eGFR determination.^13-15 Assays for cystatin C are more expensive than those for creatinine, and use of cystatin C is currently limited by reimbursement policies, but there are opportunities to reduce its costs and advocate for changes in policy.

The accuracy of the eGFR is affected by non-GFR determinants of the filtration markers, which are better understood for creatinine than for cystatin C.¹⁶ Creatinine is affected by muscle mass, diet, and drugs that interfere with tubular secretion (e.g., trimethoprim). As compared with creatinine, cystatin C is less affected by age, sex, race, and world region but is more affected by obesity, smoking, inflammation, and alterations in thyroid and glucocorticoid hormones. The accuracy of eGFRcr-cys is greater than that of either eGFRcr or eGFRcys because the use of both creatinine and cystatin C reduces the error due to the non-GFR determinants of the two filtration markers. Measured GFR (mGFR), determined on the basis of urinary or plasma clearance of an exogenous filtration marker, is more accurate than eGFR; however, such methods are typically performed only in referral centers or as part of research studies. Urinary clearance of endogenous creatinine, generally assessed from a single serum measurement and a 24-hour urine collection for measurement of the creatinine excretion rate, is readily tested but is less accurate than mGFR and may be less accurate than eGFR.

Increased albuminuria, reflecting impairment of the permselective barrier function of the glomerular capillary wall to macromolecules, is a marker of kidney damage. Increased albuminuria is seen in early stages of kidney disease due to diabetes, other glomerular diseases, or hypertension and in later stages of almost all causes of kidney disease.⁹ Numerous pathologic processes, such as inflammation, infiltration, or fibrosis, can cause albuminuria. Irrespective of the cause, albuminuria and the presence of other macromolecules in the tubular fluid may incite tubular damage and accelerate the progression of kidney disease.

Albuminuria can be assessed by means of albumin-specific assays or as a component in total urinary protein, with the use of quantitative or semiquantitative methods, in either a timed urine collection or an untimed spot urine sample. Current guidelines for albuminuria evaluation recommend determining the albumin-to-creatinine ratio in a spot urine sample as the initial test (an early-morning sample is preferred), with the result confirmed by assessing the albumin excretion rate in a timed urine collection, as appropriate for the clinical setting⁵ 
Assays for urinary albumin may be more expensive than assays for urinary total protein or dipstick testing, use of the albumin-to-creatinine ratio is limited by reimbursement policies in some countries.
Equations have been developed to estimate the urinary albumin-to-creatinine ratio from the protein-to-creatinine ratio and dipstick testing of protein, but accuracy is limited at low protein-to-creatinine ratios and low dipstick protein values.^17,18

 CLINICAL APPLICATION OF GRF AND ALBUMINURIA

* Definitions and Burden of AKD and CKD
Either a decreased GFR (<60 ml per minute per 1.73 m² of body-surface area) or increased albuminuria (albumin-to-creatinine ratio >30 mg per gram, with albumin measured in milligrams and creatinine in grams) constitutes the clinical criterion for the definitions of AKD and CKD, whereas the only criterion for AKI is a decreased GFR (indicated by oliguria or an increase in the serum creatinine level from baseline) (Table S5). The thresholds for the disease definitions do not vary according to age, clinical characteristics, or coexisting conditions.

A lower GFR and higher level of albuminuria are associated with greater risks of kidney failure that requires replacement therapy (dialysis or transplantation), a broad spectrum of treatable complications (e.g., CVD), and death^19-22 These risk relationships provide the rationale for the GFR and albuminuria thresholds used for disease definitions, as well as for the GFR and albuminuria categories used for staging of disease severity and guideline-directed care (Table S5). In CKD, a lower GFR and higher level of albuminuria are associated with an increased risk of adverse outcomes, regardless of patient age or the presence or absence of diabetes, hypertension, or obesity; thus, a decreased GFR or increased albuminuria cannot be considered normal in any of these subgroups.^23-26 A decreased GFR is an indication for adjustment of drug dosages; testing for electrolyte and acid–base disorders, anemia, and metabolic bone disease; and planning for initiation of kidney-replacement therapy. Increased albuminuria is an indication for treatment with renin–angiotensin–aldosterone inhibitors. Both are indications for strict blood-pressure control and sodium–glucose cotransporter 2 inhibition to slow the progression of kidney disease and reduce the risk of CVD.

The aging population and the obesity epidemic are leading to a growing burden of AKD and CKD globally. In Alberta, Canada, the 1-year incidence is 2.5% for AKD (0.75% for AKI and 1.75% for AKD without AKI).²⁷ 
Each disorder has been associated with a higher risk of adverse outcomes and death, as compared with no kidney disease. In the United States, the reported prevalence of CKD among adults is 11.5% overall and up to 40% among people 70 years of age or older.²⁸ By contrast, the prevalence of kidney failure that requires replacement therapy is 0.2%. Worldwide, the prevalence of CKD is 9.1% (representing approximately 700 million people).²⁹ The annual number of deaths from kidney failure is 1.2 million, with an additional 1.4 million deaths due to CVD attributed to CKD; thus, 4.6% of all deaths are due to CKD (making it the 12th leading cause of death). These results underscore the need for detection, evaluation, and treatment of even early stages of kidney disease to slow progression and prevent complications.

* Risk Factors for CVD

CVD is the most important complication of CKD. Both a decreased GFR and increased albuminuria are independent risk factors for many manifestations of CVD, including coronary heart disease, stroke, heart failure, peripheral arterial disease, and need for amputation of any lower extremity; the strongest associations are with heart failure and death from CVD.^30-32 There is a higher incidence of many CVD events in CKD than of events of kidney failure requiring replacement therapy. Including the GFR and the level of albuminuria is as important as including traditional risk factors in assessing the risk of CVD. A lower eGFRcys is more strongly associated with CVD than is a lower eGFRcr, which provides additional justification for more widespread use of cystatin C. Studies show that the occurrence of CVD events, particularly heart failure, in patients with CKD hastens the progression of kidney disease, suggesting a bidirectional relationship between CKD and CVD.^33,34 Current guidelines recommend evaluation and treatment for CKD in patients with CVD and evaluation and treatment for CVD in patients with CKD.³⁵

* Clinical Trials on Progression of Kidney Disease

There are few treatments to slow the progression of kidney disease, in part because it is difficult to conduct clinical trials of treatment for CKD. An important obstacle is that in many kidney diseases, the mean decline in the GFR is only 2 to 3 ml per minute per 1.73 m² per year, requiring a long duration of follow-up to reach the clinical end point of kidney failure. Use of predictive biomarkers (markers associated with an increased risk of the clinical end point) and surrogate end points (markers that occur earlier than clinical end points and predict the treatment effect) can help facilitate the conduct of trials. Both a decreased GFR and increased albuminuria are predictive biomarkers for the progression of kidney disease and are widely used as eligibility criteria for enrolling high-risk patients in clinical trials. The validity of these measures as surrogate end points depends on many factors.^36-38

A decline in the GFR is a step on the path to kidney failure and is therefore a meaningful end point for CKD from all causes and for all interventions. Regulatory bodies now accept as end points a 30% or 40% decline in the GFR and mean changes in the GFR (slopes) over a period of 2 to 3 years in various settings, in addition to the established surrogate end point of a doubling of the serum creatinine level (equivalent to a 57% decline in the eGFRcr). An increase in albuminuria is appealing as a surrogate end point because it can occur before a decline in the GFR, often within 6 months after the intervention is begun. However, an increase in albuminuria is limited as an end point because it is appropriate only for diseases characterized by albuminuria, interventions targeting albuminuria, and study participants with increased albuminuria at baseline and because longer follow-up may be necessary to determine changes in the GFR and the safety of the interventions. There is also interest in using changes in both albuminuria and the GFR as a combined end point.³⁹ Trials of recently approved drugs, including tolvaptan in polycystic kidney disease, glucagon-like peptide agonists and finerenone in CKD with type 2 diabetes, and several inhibitors of sodium–glucose cotransporter 2 in CKD with or without type 2 diabetes, have shown successful application of these surrogate end points for the progression of kidney disease. Trials involving patients with other chronic diseases in which CKD is common (e.g., CVD, cancer, infectious diseases, and autoimmune diseases) may also benefit from the use of these surrogate end points to evaluate the potential synergistic effects of therapeutic agents on the progression of kidney disease.

 *Risk-Prediction Instruments for CKD Outcomes

The GFR and albuminuria are used in risk-prediction instruments such as equations to guide clinical decision making. For example, the Kidney Failure Risk Equation uses the GFR, albumin-to-creatinine ratio, age, and sex to predict the 2-year and 5-year risks of kidney failure with replacement therapy for patients with a GFR of less than 60 ml per minute per 1.73 m², and its routine use is recommended by current guidelines to guide evaluation and treatment.⁴⁰ A higher predicted risk can be used to prioritize referral for a consultation with a nephrologist, multidisciplinary CKD care, or planning for kidney-replacement therapy. The GFR and level of albuminuria can also be incorporated into existing CVD risk prediction instruments to modify CVD risk predictions.⁴¹ More frequent use of these and other instruments holds promise for improving a broad spectrum of clinical outcomes across the full range of GFR and albuminuria values.

Older age predicts a lower risk of kidney failure that requires replacement therapy in the Kidney Failure Risk Equation and other instruments because of the competing effect of death, which emphasizes the difference in prognosis between older and younger people with CKD. Some people have suggested that the GFR threshold for the definition of CKD should be age-adapted (a lower GFR threshold for older people than for younger people) because of the higher prevalence of CKD and lower relative risk of kidney failure among older people.⁴² In our view, the absolute and the relative risks associated with all CKD outcomes, not only kidney failure, should be considered, and the evaluation and management of CKD, not the definition, should be adapted for age and other risk factors with the use of appropriate risk-prediction instruments.⁴³

^CONCLUSIONS

The GFR and level of albuminuria are powerful measures for detecting and staging AKD and CKD and for predicting the risk of kidney-disease progression and CVD, but they remain underused.
We suggest that greater use of these measures can lead to further advances in clinical practice, research, and public health.

 

NOTE: Tables, Figures, References (43) in original article.

 

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