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CKD, Diabetes Care
CKD, Diabetes Care
CKD, Diabetes Care
with severely increased al- normal urinary albumin-to- 11.5b For people with type 2 diabe-
buminuria (urinary albumin- creatinine ratio (<30 mg/g tes and diabetic kidney dis-
to-creatinine ratio $300 mg/g creatinine), and normal esti- ease, use of a sodium–glucose
creatinine) and/or estimated mated glomerular filtration cotransporter 2 inhibitor is rec-
glomerular filtration rate rate. A ommended to reduce chronic
<60 mL/min/1.73 m2 . A 11.4d Do not discontinue renin- kidney disease progression
11.4b Periodically monitor serum cre- angiotensin system blockade and cardiovascular events in
atinine and potassium levels for increases in serum creati- patients with an estimated
for the development of in- nine (#30%) in the absence glomerular filtration rate $20
creased creatinine and hyper- of volume depletion. A mL/min/1.73 m2 and urinary
kalemia when ACE inhibitors, 11.5a For people with type 2 diabe- albumin ranging from normal
angiotensin receptor blockers, tes and diabetic kidney dis- to 200 mg/g creatinine. B
and mineralocorticoid receptor ease, use of a sodium–glucose 11.5c In people with type 2 diabetes
antagonists are used, or hypo- cotransporter 2 inhibitor is rec- and diabetic kidney disease,
kalemia when diuretics are ommended to reduce chronic consider use of sodium–glucose
used. B kidney disease progression cotransporter 2 inhibitors (if
11.4c An ACE inhibitor or an angio- and cardiovascular events in estimated glomerular filtration
tensin receptor blocker is not patients with an estimated rate is $20 mL/min/1.73 m2),
recommended for the primary glomerular filtration rate a glucagon-like peptide 1 ago-
prevention of chronic kidney $20 mL/min/1.73 m2 and nist, or a nonsteroidal mineralo-
disease in people with diabetes urinary albumin $200 mg/g corticoid receptor antagonist
who have normal blood pressure, creatinine. A (if estimated glomerular filtration
diabetesjournals.org/care Chronic Kidney Disease and Risk Management S193
rate is $25 mL/min/1.73 m2) (diabetic kidney disease) in adults, >20% between measurements in uri-
additionally for cardiovascular which occurs in 20–40% of people with nary albumin excretion, two of three
risk reduction. A diabetes (1,3–5). Diabetic kidney disease specimens of UACR collected within a
11.5d In people with chronic kidney typically develops after a diabetes dura- 3- to 6-month period should be abnormal
disease and albuminuria who tion of 10 years in type 1 diabetes (the before considering a patient to have
are at increased risk for cardio- most common presentation is 5–15 years moderately or severely elevated albu-
vascular events or chronic kidney after the diagnosis of type 1 diabetes) minuria (1,2,13,14). Exercise within 24 h,
disease progression, a nonsteroi- but may be present at diagnosis of type 2 infection, fever, congestive heart failure,
dal mineralocorticoid receptor diabetes. CKD can progress to end-stage marked hyperglycemia, menstruation,
antagonist shown to be effective renal disease (ESRD) requiring dialysis or and marked hypertension may elevate
kidney transplantation and is the leading UACR independently of kidney damage
in clinical trials is recommended
cause of ESRD in the U.S. (6). In addition, (15).
to reduce chronic kidney disease
diabetic kidney disease may be present possible causes other than diabetes) Lastly, it should be noted that ACE
at diagnosis or without retinopathy in may also affect these decisions (24). inhibitors and ARBs are commonly not
type 2 diabetes. Reduced eGFR without dosed at maximum tolerated doses
albuminuria has been frequently re- ACUTE KIDNEY INJURY because of fear that serum creatinine
ported in type 1 and type 2 diabetes will rise. As noted above, this is an error.
Acute kidney injury (AKI) is diagnosed by
and is becoming more common over Note that in all clinical trials demonstrat-
time as the prevalence of diabetes in- a 50% or greater sustained increase in se-
rum creatinine over a short period of ing efficacy of ACE inhibitors and ARBs in
creases in the U.S. (3,4,18,19). slowing kidney disease progression, the
An active urinary sediment (containing time, which is also reflected as a rapid
decrease in eGFR (25,26). People with di- maximum tolerated doses were used—
red or white blood cells or cellular casts), not very low doses that do not provide
rapidly increasing albuminuria or total abetes are at higher risk of AKI than
benefit. Moreover, there are now studies
proteinuria, the presence of nephrotic those without diabetes (27). Other risk
demonstrating outcome benefits on both
syndrome, rapidly decreasing eGFR, or factors for AKI include preexisting CKD,
kidney function may be detected by in- Assessment of Comorbidities,” for further Glycemic Targets
information on immunization). Intensive lowering of blood glucose with
creases in albuminuria before changes
the goal of achieving near-normoglycemia
in eGFR (43), and this also significantly
Prevention has been shown in large randomized
affects cardiovascular risk. Moreover, an
The only proven primary prevention inter- studies to delay the onset and pro-
initial reduction of >30% from baseline,
ventions for CKD are blood glucose and gression of albuminuria and reduce
subsequently maintained over at least 2 eGFR in people with type 1 diabetes
blood pressure control. There is no evi-
years, is considered a valid surrogate for (51,52) and type 2 diabetes (1,53–58).
dence that renin-angiotensin-aldosterone
renal benefit by the Division of Cardiology Insulin alone was used to lower blood
system (RAAS) inhibitors or any other
and Nephrology of the U.S. Food and glucose in the Diabetes Control and
interventions prevent the development
Drug Administration (FDA) (10). Contin- of diabetic kidney disease. Thus, the Complications Trial (DCCT)/Epidemiology
ued surveillance can assess both response American Diabetes Association does of Diabetes Interventions and Complica-
to therapy and disease progression and not recommend routine use of these tions (EDIC) study of type 1 diabetes,
may aid in assessing participation in ACE medications solely for the purpose of while a variety of agents were used
inhibitor or ARB therapy. In addition, in prevention of the development of di- in clinical trials of type 2 diabetes,
clinical trials of ACE inhibitors or ARB abetic kidney disease. supporting the conclusion that lower-
therapy in type 2 diabetes, reducing albu- ing blood glucose itself helps prevent
minuria to levels <300 mg/g creatinine INTERVENTIONS CKD and its progression. The effects
or by >30% from baseline has been asso- Nutrition of glucose-lowering therapies on CKD
ciated with improved renal and cardiovas- For people with non-dialysis-dependent have helped define A1C targets (see
CKD, dietary protein intake should be Table 6.2).
cular outcomes, leading some to suggest
0.8 g/kg body weight per day (the rec- The presence of CKD affects the risks
that medications should be titrated to
ommended daily allowance) (1). Com- and benefits of intensive lowering of
maximize reduction in UACR. Data from
pared with higher levels of dietary protein blood glucose and a number of specific
post hoc analyses demonstrate less ben- glucose-lowering medications. In the Ac-
intake, this level slowed GFR decline with
efit on cardiorenal outcomes at half tion to Control Cardiovascular Risk in Dia-
evidence of a greater effect over time.
doses of RAS blockade (44). In type 1 di- betes (ACCORD) trial of type 2 diabetes,
Higher levels of dietary protein intake
abetes, remission of albuminuria may (>20% of daily calories from protein or adverse effects of intensive management
occur spontaneously, and cohort studies >1.3 g/kg/day) have been associated of blood glucose levels (hypoglycemia
evaluating associations of change in al- with increased albuminuria, more rapid and mortality) were increased among
buminuria with clinical outcomes have kidney function loss, and CVD mortality people with kidney disease at baseline
reported inconsistent results (45,46). and therefore should be avoided. Reduc- (59,60). Moreover, there is a lag time
The prevalence of CKD complications ing the amount of dietary protein below of at least 2 years in type 2 diabetes to
correlates with eGFR (42). When eGFR is the recommended daily allowance of over 10 years in type 1 diabetes for the
<60 mL/min/1.73 m2, screening for 0.8 g/kg/day is not recommended be- effects of intensive glucose control to
complications of CKD is indicated (Table cause it does not alter blood glucose manifest as improved eGFR outcomes
11.1). Early vaccination against hepatitis levels, cardiovascular risk measures, or (56,60,61). Therefore, in some people
B virus is indicated in individuals likely the course of GFR decline (47). with prevalent CKD and substantial co-
to progress to ESRD (see Section 4, Restriction of dietary sodium (to <2,300 morbidity, target A1C levels may be less
“Comprehensive Medical Evaluation and mg/day) may be useful to control blood intensive (1,62).
S196 Chronic Kidney Disease and Risk Management Diabetes Care Volume 46, Supplement 1, January 2023
Blood Pressure and Use of RAAS moderately increased albuminuria with- selecting antihyperglycemia agents (see
Inhibitors out hypertension, outcome trials have Section 9, “Pharmacologic Approaches to
RAAS inhibition remains a mainstay of not been performed in this setting to Glycemic Treatment”).
management for people with diabetic determine whether they improve renal
kidney disease with albuminuria and for outcomes. Moreover, two long-term, dou- Selection of Glucose-Lowering
the treatment of hypertension in people ble-blind studies demonstrated no reno- Medications for People With Chronic
with diabetes (with or without diabetic protective effect of either ACE inhibitors Kidney Disease
kidney disease). Indeed, all the trials or ARBs in type 1 and type 2 diabetes For people with type 2 diabetes and es-
that evaluated the benefits of SGLT2 in- among those who were normotensive tablished CKD, special considerations for
hibition or nonsteroidal mineralocorti- with or without high albuminuria (for- the selection of glucose-lowering medica-
coid receptor antagonist effects were merly microalbuminuria) (78,79). tions include limitations to available med-
done in individuals who were being Absent kidney disease, ACE inhibitors ications when eGFR is diminished and a
A number of large cardiovascular out- (28). Additionally, the development of 0.55–0.92; P 5 0.009). Finally, all-cause
comes trials in people with type 2 dia- the primary end point, which included mortality was decreased in the dapagli-
betes at high risk for CVD or with chronic dialysis for $30 days, kidney flozin group compared with the placebo
existing CVD examined kidney effects as transplantation or eGFR <15 mL/min/ group (P < 0.004).
secondary outcomes. These trials in- 1.73 m2 sustained for $30 days by cen- In addition to renal effects, while
clude EMPA-REG OUTCOME [BI 10773 tral laboratory assessment, doubling SGLT2 inhibitors demonstrated reduced
(Empagliflozin) Cardiovascular Outcome from the baseline serum creatinine aver- risk of heart failure hospitalizations,
Event Trial in Type 2 Diabetes Mellitus age sustained for $30 days by central some also demonstrated cardiovascular
Patients], CANVAS (Canagliflozin Cardio- laboratory assessment, or renal death or risk reduction. GLP-1 RAs clearly demon-
vascular Assessment Study), LEADER (Lira- cardiovascular death, was reduced by strated cardiovascular benefits. Namely,
glutide Effect and Action in Diabetes: 30%. This benefit was on background in the EMPA-REG OUTCOME, CANVAS,
Evaluation of Cardiovascular Outcome Re- ACE inhibitor or ARB therapy in >99% of Dapagliflozin Effect on Cardiovascular
event information, for these agents. Addi- in people with an eGFR $20 mL/min/ and the mean albuminuria was 852 mg/g
tional clinical trials focusing on CKD and 1.73 m2. (interquartile range 446–1,634 mg/g).
cardiovascular outcomes in people with Of note, GLP-1 RAs may also be used The primary end point was reduced
CKD are ongoing and will be reported in at low eGFR for cardiovascular protection with finerenone compared with pla-
the next few years. but may require dose adjustment (113). cebo (HR 0.82 [95% CI 0.73–0.93]; P 5
For people with type 2 diabetes and 0.001), as was the key secondary com-
CKD, the selection of specific agents may Renal and Cardiovascular Outcomes posite of cardiovascular outcome (HR
depend on comorbidity and CKD stage. of Mineralocorticoid Receptor 0.86 [95% CI 0.75–0.99]; P 5 0.03).
SGLT2 inhibitors may be more useful for Antagonists in Chronic Kidney Hyperkalemia resulted in 2.3% discontin-
individuals at high risk of CKD progres- Disease uation in the study group compared
sion (i.e., with albuminuria or a history of MRAs historically have not been well with 0.9% in the placebo group. How-
documented eGFR loss) (Fig. 9.3) due to studied in diabetic kidney disease ever, the study was completed, and
the placebo group (HR 0.64 [95% CI found to reduce cost, improve quality of 13. Gomes MB, Gonçalves MF. Is there a
0.41–0.995]). There was a higher inci- care, and delay dialysis (120). However, physiological variability for albumin excretion
rate? Study in patients with diabetes type 1 and
dence of hyperkalemia in the finerenone other specialists and health care professio- non-diabetic individuals. Clin Chim Acta 2001;304:
group, 10.8% vs. 5.3%, although only 1.2% nals should also educate their patients 117–123
of the 3,686 individuals on finerenone about the progressive nature of CKD, the 14. Naresh CN, Hayen A, Weening A, Craig JC,
stopped the study due to hyperkalemia kidney preservation benefits of proactive Chadban SJ. Day-to-day variability in spot urine
treatment of blood pressure and blood albumin-creatinine ratio. Am J Kidney Dis 2013;
(0.6% vs. 0.4% of the placebo group).
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