Review of Recent Literature in Hypertension: Updated Clinical Practice Guidelines for Chronic Kidney Disease Now Include Albuminuria in the Classification System
Chronic kidney disease (CKD) is a worldwide public health problem, affecting 10% to 15% of the adult population. In 2002, the National Kidney Foundation (NKF) first published their recommendations for staging of CKD. While this staging system, based solely on glomerular filtration rate (GFR), has since become the internationally accepted standard, there is increasing recognition that protein, particularly albumin excretion, which was not included in the original staging system, is also important in assessing cardiovascular (CV) and renal progression risk in patients with CKD. Based on this limitation and other important research that has accumulated in the past decade, the Kidney Disease Improving Global Outcomes (KDIGO) organization recently published an updated Clinical Practice Guideline (CPG) on the evaluation and management of CKD. These recommendations have been abstracted and further discussed in the internal medicine literature, and that publication is reviewed.
It is clear that the authors have provided comprehensive and practical advice, particularly in the areas of classification and evaluation. Based on our current fund of knowledge, the recommendations are biologically plausible and supported by observational and clinical trial data as well as expert opinion. It remains striking, however, how few of these recommendations can be supported with the highest quality evidence. While we encourage providers to make use of this classification and evaluation scheme, we also hope that the distribution of these guidelines will stimulate greater research to prove (or disprove) the oftentimes untested hypotheses that support many of these individual recommendations.
Recommendations for the Definition and Classification of CKD
According to these guidelines, CKD can be defined as “abnormalities of kidney structure or function, present for at least 3 months, with implications for health.” Abnormalities of kidney function include: decreased GFR (<60 mL/min/1.73 m2 body surface area), the presence of significant albuminuria (albumin excretion rate [AER] at least 30 mg/d or albumin:creatinine ratio [ACR] at least 30 mg/g creatinine), or other markers of kidney disease such as urinary sediment abnormalities, evidence of tubular disorders, histological abnormalities, structural abnormalities seen on imaging, or a history of kidney transplantation.
Of note, this recommendation is not graded and is the result of expert opinion. One potential criticism of this definition is the inclusion of anatomical issues identified on imaging studies that may not be of clinical importance, but, as the authors emphasize, the requirement that these abnormalities have “implications for health” hopefully allows clinicians to make an individualized determination about whether these abnormalities are clinically significant and thus represent true CKD.
Arguably, the revised classification system of CKD severity is the most important contribution of this CPG. In the previous staging system, staging of CKD relied solely on the determination of GFR; however, in these updated guidelines, the staging system now includes degree of albuminuria in addition to GFR as a measure of severity. Now, each patient is classified into two domains. There is a G (GFR domain) and an A (albuminuria) domain.
The G domain has retained similar cutoffs to the previous guidelines, with the important addition of subdividing stage 3 into stages 3a and 3b, noted below:
- G1=normal or high (GFR of at least 90)
- G2=mildly decreased (GFR 60–89)
- G3a=mildly to moderately decreased (GFR 45–59)
- G3b=moderately to severely decreased (GFR 30–44)
- G4=severely decreased (GFR 15–29)
- G5=kidney failure (GFR <15)
For albumin excretion, the following classification is proposed:
- A1=normal to mildly increased (AER <30 mg/d or ACR <30 mg albumin/g creatinine)
- A2=moderately increased (AER 30–300 mg/d or ACR 30–300 mg/g)
- A3=severely increased (AER >300 mg/d or ACR >300 mg/g)
The updated classification system is likely to have the greatest impact on patients with stage 3 CKD. Stage 3 is far and away the most prevalent stage of CKD, and being able to subdivide these patients into those with greater or lesser kidney function abnormalities and albumin excretion categories is clinically important. Based on observational data, the prognosis for a patient with G3aA1 disease is far different from G3bA3 disease (and the various iterations between). Being able to subdivide this large group of patients into multiple severity strata marks a huge improvement in the clinical utility of these guidelines.
The authors have given the concept of this new severity classification system a grade 1b. Certainly, the addition of albuminuria to the classification system is supported by a large number of observational studies linking degree of albumin excretion to CV and renal prognosis in CKD. However, it is important to highlight the fact that while the concept of graded risk with decreasing GFR and increasing albuminuria is highly defendable, the exact cutoffs employed are largely arbitrary.
Recommendations for Evaluation of GFR and Albuminuria
The KDIGO guidelines call for use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to estimate GFR. Use of a single equation certainly can help facilitate consistency across the health care delivery system, but proponents of the Modification of Diet and Renal Disease (MDRD) Study equation will point out that the superiority of CKD-EPI over MDRD has not been well-established. These guidelines also suggest, albeit with a grade 2C recommendation, use of cystatin C measurement to confirm the diagnosis of CKD specifically in patients with CKD-EPI GFR 45 to 60 and no other evidence of CKD. Up to one third of patients with no albuminuria and an estimated GFR in this range will have a GFR >60 when measured using cystatin C, and accordingly may not need to be treated as having CKD. As admitted by the authors, however, this is an area of great controversy and limited data. Despite the controversy, and with often limited ability to measure cystatin C, we believe the clinical implications of this recommendation are limited since these patients by definition have at most G3aA1 disease and as such do not need to be treated overly aggressively; carefully monitoring for progression should be able to differentiate those with true clinically meaningful CKD over time.
For albumin excretion, the authors have suggested that laboratories move toward reporting ACR in untimed (spot) urine samples in addition or instead of albumin concentration. The use of albuminuria rather than proteinuria is suggested for a variety of reasons, perhaps most important of which is that it is a more sensitive marker for low-grade but clinically important protein excretion. The authors suggest that the term microalbuminuria should no longer be utilized since albumin excretion at any level is indicative of risk. This is somewhat of a semantic argument and whether using a label of “A2” rather than “microalbuminuria” provides greater precision and clinical meaningfulness is not abundantly clear.
Recommendations for Monitoring CKD
Recommendations for frequency of monitoring for CKD progression will depend on the severity of disease. Patients at the lower end of the severity classification (G1A1, G1A2, G2A1, G2A2, G3aA1) need only be monitored once yearly. As severity progresses, monitoring frequency should increase to twice yearly (G1A3, G2A3, G3aA2, G3bA1), thrice yearly (G3aA3, G3bA2, G3bA3, G4A1, G4A2), or at least quarterly (G4A3, G5A1, G5A2, G5A3). While the exact frequency of monitoring for each stage appears to be arbitrary and will be difficult for clinicians to remember and employ, the concept is a sound one; increasing severity of CKD should lead to increased monitoring.
Progression of CKD is defined as a change in GFR category and a 25% decrease in GFR. This practical definition is somewhat cumbersome, but should decrease the risk of small fluctuations in GFR leading to intensified therapy due to the crossing of an arbitrary cutpoint.
Management of CKD
In terms of blood pressure (BP), these guidelines recommend that antihypertensive medications be initiated for patients with CKD and AER (or ACR) <30 (A1) who have a BP consistently >140/90 mm Hg, and that <140/90 mm Hg should be the BP goal for these patients regardless of the cause of CKD. For patients with CKD and AER (or ACR) >30 (A2 or A3), antihypertensive medications should be initiated in those who have a BP consistently >130/80 mm Hg and that <130/80 mm Hg should be the BP goal in these patients, regardless of the cause of CKD.
The data supporting these BP goals are difficult to interpret and have been previously reviewed in this column. We agree that there is relatively strong evidence supporting a BP goal <140/90 mm Hg for patients with A1 disease and a goal of <130/80 mm Hg for patients with A3 disease. The KDIGO guidelines also suggest a BP goal of <130/80 mm Hg for patients with A2 disease, but this is not well supported by the available data. Most of the studies that have demonstrated a reduction in renal progression with more intensive BP goals have used a definition of at least 300 g/d, and not an AER >30 mg/d. In most studies, patients with <300 g/d of proteinuria do not seem to have derived significant clinical benefit from more intensive BP reduction. Data from the Systolic Prevention Intervention (SPRINT) trial, when it becomes available, may help to determine the validity of these BP recommendations.
The guidelines also appropriately recommend that an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) be used in both diabetic and nondiabetic adults with CKD and UAE >300 mg/d. Consistent with our most recent clinical trial data, the guidelines also recommend against the use of dual renin-angiotensin-system blockade, specifically avoiding the combining of an ACE inhibitor, ARB, or direct renin inhibitor.
Finally, the guidelines suggest that patients with CKD are at increased CV risk and while they stop short of stating that CKD is a “CHD risk equivalent,” they recommend increased vigilance in identifying and treating known CV risk factors such as smoking, dyslipidemia, and diabetes mellitus in patients with CKD of any severity.
By including degree of albumin excretion and subdividing stage 3 CKD into those with GFR < or >45 cc/min, the updated KDIGO guidelines give health care providers a more useful tool for assessing severity of CKD while still retaining enough simplicity to be practical. That said, the BP goals provided represent a continuing point of controversy and we await high-quality prospective randomized clinical trial data to further define the true BP “sweet spot” for best ameliorating renal functional decline in patients with and without differing degrees of proteinuria.