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Albuminuria categories
Description and range
A1 A2 A3
Low risk (if no other markers of kidney disease, no CKD) High risk
Figure 11.1—Risk of CKD progression, frequency of visits, and referral to nephrology according to GFR and albuminuria. The numbers in the boxes
are a guide to the frequency of screening or monitoring (number of times per year). Green reflects no evidence of CKD by estimated GFR or albu-
minuria, with screening indicated once per year. For monitoring of prevalent CKD, suggested monitoring varies from once per year (yellow) to four
times or more per year (i.e., every 1–3 months, [deep red]) according to risks of CKD progression and CKD complications (e.g., cardiovascular dis-
ease, anemia, hyperparathyroidism). These are general parameters based only on expert opinion and underlying comorbid conditions, and disease
state must be taken into account, as well as the likelihood of impacting a change in management for any individual. CKD, chronic kidney disease;
GFR, glomerular filtration rate. Reprinted and adapted from de Boer et al. (1).
11.4b Periodically monitor for increased 11.5b For people with type 2 diabe- Potassium levels should be moni-
serum creatinine and potassium levels tes and CKD, use of an SGLT2 inhibi- tored. A
when ACE inhibitors, ARBs, and miner- tor is recommended to reduce CKD 11.6 In people with CKD who have
alocorticoid receptor antagonists are progression and cardiovascular events $300 mg/g urinary albumin, a reduc-
used, or for hypokalemia when diu- in individuals with eGFR $20 mL/min/ tion of 30% or greater in mg/g urinary
retics are used. B 1.73 m2 and urinary albumin rang- albumin is recommended to slow CKD
11.4c An ACE inhibitor or an ARB is ing from normal to 200 mg/g creati- progression. C
not recommended for the primary pre- nine. B 11.7 For people with non–dialysis-
vention of CKD in people with diabetes 11.5c For cardiovascular risk reduc- dependent stage G3 or higher CKD,
who have normal blood pressure, nor- tion in people with type 2 diabetes dietary protein intake should be aimed
mal UACR (<30 mg/g creatinine), and and CKD, consider use of an SGLT2 to a target level of 0.8 g/kg body
normal eGFR. A inhibitor (if eGFR is $20 mL/min/ weight per day. A For individuals on
11.4d Do not discontinue renin- 1.73 m2), a glucagon-like peptide 1 dialysis, 1.0–1.2 g/kg/day of dietary
angiotensin system blockade for mild agonist, or a nonsteroidal mineralo- protein intake should be considered
to moderate increases in serum creati- corticoid receptor antagonist (if eGFR since protein energy wasting is a ma-
nine (#30%) in the absence of signs of is $25 mL/min/1.73 m2). A jor problem in some individuals on
extracellular fluid volume depletion. A 11.5d As people with CKD and albu- dialysis. B
11.5a For people with type 2 diabe- minuria are at increased risk for 11.8 Individuals should be referred
tes and CKD, use of a sodium–glucose cardiovascular events and CKD pro- for evaluation by a nephrologist if
cotransporter 2 (SGLT2) inhibitor is gression, a nonsteroidal mineralocor- they have continuously increasing
recommended to reduce CKD pro- ticoid receptor antagonist that has urinary albumin levels and/or con-
gression and cardiovascular events in been shown to be effective in clinical tinuously decreasing eGFR and/or if
individuals with eGFR $20 mL/min/ trials is recommended to reduce car- the eGFR is <30 mL/min/1.73 m2. A
1.73 m2 and urinary albumin $200 mg/g diovascular events and CKD progres- 11.9 Promptly refer to a nephrologist
creatinine. A sion (if eGFR is $25 mL/min/1.73 m2). for uncertainty about the etiology of
diabetesjournals.org/care Chronic Kidney Disease and Risk Management S221
kidney disease, difficult management because it will ultimately need to be and would support better clinical deci-
issues, and rapidly progressing kidney done. sions than either marker alone.
disease. B Normal level of urine albumin excre-
tion is defined as <30 mg/g creatinine, DIAGNOSIS OF DIABETIC KIDNEY
moderately elevated albuminuria is de- DISEASE
EPIDEMIOLOGY OF DIABETES AND fined as $30–300 mg/g creatinine, and Diabetic kidney disease is a clinical diag-
CHRONIC KIDNEY DISEASE severely elevated albuminuria is defined nosis made based on the presence of
as $300 mg/g creatinine. However, UACR albuminuria and/or reduced eGFR in
Chronic kidney disease (CKD) is diag-
is a continuous measurement, and differ- the absence of signs or symptoms of
nosed by the persistent elevation of uri-
ences within the normal and abnormal other primary causes of kidney damage.
nary albumin excretion (albuminuria),
ranges are associated with kidney and
low estimated glomerular filtration rate The typical presentation of diabetic kid-
cardiovascular outcomes (6,10,11). Fur- ney disease is considered to include
(eGFR), or other manifestations of kid-
thermore, because of high biological vari- long-standing duration of diabetes, reti-
more closely associated with risk but is risks of progressive CKD and other poor tolerated doses, and achievement of blood
also more complex and does not trans- health outcomes (34). pressure targets. Early changes in kidney
late directly to treatment decisions (1). Elevations in serum creatinine (up to function may be detected by increases in
Thus, based on the current classification 30% from baseline) with renin-angioten- albuminuria before changes in eGFR (41),
system, both eGFR and albuminuria sin system (RAS) blockers (such as ACE and this also significantly affects cardiovas-
must be quantified to guide treatment inhibitors and ARBs) must not be con- cular risk. Moreover, an initial reduction of
decisions. Quantification of eGFR levels fused with AKI (35). An analysis of the >30% from baseline, subsequently main-
is essential for modifications of medica- Action to Control Cardiovascular Risk in tained over at least 2 years, is considered
tion dosages or restrictions of use (Fig. Diabetes Blood Pressure (ACCORD BP) a valid surrogate for renal benefit by
11.1) (23,24), and the degree of albu- trial demonstrated that participants ran- the Division of Cardiology and Nephrol-
minuria should influence the choice of domized to intensive blood pressure ogy of the U.S. Food and Drug Adminis-
antihypertensive medications (see Sec- lowering with up to a 30% increase in se- tration (FDA) (9). Continued surveillance
tion 10, “Cardiovascular Disease and rum creatinine did not have any increase can assess both response to therapy and
trials have not been performed in this set- Direct Renal Effects of Glucose- not be initiated for individuals with an
ting to determine whether they improve Lowering Medications eGFR <45 mL/min/1.73 m2, and 5) met-
renal outcomes. Moreover, two long-term, Some glucose-lowering medications also formin should be temporarily discontin-
double-blind studies demonstrated no re- have effects on the kidney that are di- ued at the time of or before iodinated
noprotective effect of either ACE inhibi- rect, i.e., not mediated through glycemia. contrast imaging procedures in individu-
tors or ARBs among people with type 1 For example, SGLT2 inhibitors reduce re- als with eGFR 30–60 mL/min/1.73 m2.
and type 2 diabetes who were normoten- nal tubular glucose reabsorption, weight, A number of recent studies have
systemic blood pressure, intraglomerular shown cardiovascular protection from
sive with or without high albuminuria
pressure, and albuminuria and slow GFR SGLT2 inhibitors and GLP-1 RAs as well as
(formerly microalbuminuria, 30–299 mg/g
loss through mechanisms that appear in- renal protection from SGLT2 inhibitors
creatinine) (73,74).
dependent of glycemia (31,81–84). More- and possibly from GLP-1 RAs. Selection of
It should be noted that ACE inhibitors
over, recent data support the notion that which glucose-lowering medications to
and ARBs are commonly not dosed at
SGLT2 inhibitors reduce oxidative stress use should be based on the usual criteria
maximum tolerated doses because of
Regular
risk factor
Lifestyle reassessment
(every 3–6
Healthy diet Physical activity Smoking cessation Weight management months)
Figure 11.2—Holistic approach for improving outcomes in people with diabetes and CKD. Icons presented indicate the following benefits: BP cuff,
BP lowering; glucometer, glucose lowering; heart, cardioprotection; kidney, kidney protection; scale, weight management. eGFR is presented in
units of mL/min/1.73 m2. *ACEi or ARB (at maximal tolerated doses) should be first-line therapy for hypertension when albuminuria is present.
Otherwise, dihydropyridine calcium channel blocker or diuretic can also be considered; all three classes are often needed to attain BP targets.
†Finerenone is currently the only ns-MRA with proven clinical kidney and cardiovascular benefits. ACEi, angiotensin-converting enzyme inhibitor;
ACR, albumin-to creatinine ratio; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; CCB, cal-
cium channel blocker; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist;
HTN, hypertension; MRA, mineralocorticoid receptor antagonist; ns-MRA, nonsteroidal mineralocorticoid receptor antagonist; PCSK9i, proprotein
convertase subtilisin/kexin type 9 inhibitor; RAS, renin-angiotensin system; SGLT2i, sodium–glucose cotransporter 2 inhibitor; T1D, type 1 diabetes;
T2D, type 2 diabetes. Reprinted from de Boer et al. (1).
semaglutide reduced the risk of new or or cardiovascular death (29,103). It was infarction, or nonfatal stroke (29,101,
worsening nephropathy (a composite of stopped early due to positive efficacy and 104).
persistent UACR >300 mg/g creatinine, showed a 32% risk reduction for develop- A second trial in advanced diabetic
doubling of serum creatinine, or ESKD) by ment of ESKD over control (29). Addition- kidney disease was the Dapagliflozin
36% (each P < 0.01). These analyses were ally, the development of the primary end and Prevention of Adverse Outcomes in
limited by evaluation of study populations point, which included dialysis for $30 Chronic Kidney Disease (DAPA-CKD)
not selected primarily for CKD and examina- days, kidney transplantation or eGFR <15 study (105). This trial examined a cohort
tion of renal effects as secondary outcomes. mL/min/1.73 m2 sustained for $30 days similar to that in CREDENCE except
Three large clinical trials of SGLT2 in- by central laboratory assessment, dou- 67.5% of the participants had type 2
hibitors have focused on people with bling from the baseline serum creatinine diabetes and CKD (the other one-third
CKD and assessment of primary renal average sustained for $30 days by central had CKD without type 2 diabetes), and
outcomes. Canagliflozin and Renal Events laboratory assessment, or renal death or the end points were slightly different.
in Diabetes with Established Nephropathy cardiovascular death, was reduced by The primary outcome was time to the
Clinical Evaluation (CREDENCE), a placebo- 30%. This benefit was on background first occurrence of any of the compo-
controlled trial of canagliflozin among ACE inhibitor or ARB therapy in >99% nents of the composite, including $50%
4,401 adults with type 2 diabetes, UACR of the participants (29). Moreover, in sustained decline in eGFR or reaching
$300–5,000 mg/g creatinine, and eGFR this advanced CKD group, there were ESKD or cardiovascular death, or renal
range 30–90 mL/min/1.73 m2 (mean clear benefits on cardiovascular out- death. Secondary outcome measures in-
eGFR 56 mL/min/1.73 m2 with a mean al- comes demonstrating a 31% reduction cluded time to the first occurrence of
buminuria level of >900 mg/day), had a in cardiovascular death or heart failure any of the components of the compos-
primary composite end point of ESKD, hospitalization and a 20% reduction in ite kidney outcome ($50% sustained
doubling of serum creatinine, or renal cardiovascular death, nonfatal myocardial decline in eGFR or reaching ESKD or
S226 Chronic Kidney Disease and Risk Management Diabetes Care Volume 47, Supplement 1, January 2024
renal death), time to the first occur- although 28% of CANVAS participants (109) and analyses from the EMPEROR
rence of either of the components of with CKD did not have diagnosed ASCVD heart failure trials suggest that SGLT2 in-
the cardiovascular composite (cardio- (32). hibitors are safe and effective at eGFR
vascular death or hospitalization for Based on evidence from the CRE- levels of >20 mL/min/1.73 m2. The Em-
heart failure), and time to death from DENCE, DAPA-CKD, and EMPA-KIDNEY pagliflozin Outcome Trial in Patients With
any cause. The trial had 4,304 partici- trials, as well as secondary analyses of Chronic Heart Failure With Preserved
pants with a mean eGFR at baseline cardiovascular outcomes trials with SGLT2 Ejection Fraction (EMPEROR-Preserved)
of 43.1 ± 12.4 mL/min/1.73 m2 (range inhibitors, cardiovascular and renal events enrolled 5,998 participants (110), and the
25–75 mL/min/1.73 m2) and a median are reduced with SGLT2 inhibitor use in Empagliflozin Outcome Trial in Patients
UACR of 949 mg/g (range 200–5,000 individuals with an eGFR of 20 mL/min/ With Chronic Heart Failure and a Reduced
mg/g). There was a significant benefit 1.73 m2, independent of glucose-lowering Ejection Fraction (EMPEROR-Reduced) en-
by dapagliflozin for the primary end effects (101,104). rolled 3,730 participants (111); enrollment
point (hazard ratio [HR] 0.61 [95% CI While there is clear cardiovascular criteria included eGFR >60 mL/min/1.73
baseline over at least 4 weeks, or renal dose from 10 to 20 mg once daily was en- (with the exclusion of those with heart
death. A prespecified secondary outcome couraged after 1 month, provided the se- failure with reduced ejection fraction).
was time to first occurrence of the com- rum potassium level was #4.8 mmol/L
posite end point of cardiovascular death and eGFR was stable. The mean age of REFERRAL TO A NEPHROLOGIST
or nonfatal cardiovascular events (myocar- participants was 64.1 years (31% were fe- Health care professionals should con-
dial infarction, stroke, or hospitalization male), and the median follow-up duration sider referral to a nephrologist if the in-
for heart failure). Other secondary out- was 3.4 years. The median A1C was dividual with diabetes has continuously
comes included all-cause mortality, time 7.7%, the mean systolic blood pressure rising UACR levels and/or continuously
to all-cause hospitalizations, and change was 136 mmHg, and the mean GFR was declining eGFR, if there is uncertainty
in UACR from baseline to month 4, and 67.8 mL/min/1.73 m2. People with heart about the etiology of kidney disease, for
time to first occurrence of the following failure with a reduced ejection fraction difficult management issues (anemia,
composite end point: onset of kidney and uncontrolled hypertension were secondary hyperparathyroidism, signifi-
failure, a sustained decrease in eGFR excluded. cant increases in albuminuria in spite of
mortality and end-stage renal disease in diabetes in the Diabetes Control and Comp- creatinine: is this a cause for concern? Arch
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