CKD and Diabetes: Tips & Tricks

CKD and Diabetes: Tips & Tricks
Usama Ragab Youssif, MD
Lecturer of Medicine

Case Question 1
A 50-year-old female was diagnosed with type 2 diabetes at age 30.
She has taken medications as prescribed since diagnosis. The fact that
she has confirmed diabetes puts this patient at:
A. Higher risk for kidney failure and CVD
B. Higher risk for kidney failure only
C. Higher risk for CVD only
D. None of the above

CKD-CVD-
Diabetes
Link: CKD is
a Disease
Multiplier

CKD Risk Factors*
Modifiable
• Diabetes
• Hypertension
• History of AKI
• Frequent NSAID use
Non-Modifiable
• Family history of kidney
disease, diabetes, or
hypertension
• Age 60 or older (GFR declines
normally with age)
• Race/U.S. ethnic minority
status
*Partial list
AKI, acute kidney injury

Diabetes and
hypertension
are
leading causes
of kidney
failure
ESRD, end stage renal disease
USRDS ADR, 2007
Incident ESRD rates, by primary diagnosis, adjusted for age, gender, & race.

*ASVD was defined as the first occurrence of AMI, CVD/TIA, or PVD.
Incidence/100
Patient-Yr
x 2.8
x 2.3
x 1.7
x 2.1
x 2.0
x 2.5
Risk for Cardiovascular Events Is Greatest When Both
Diabetes and CKD Are Present
 Retrospective analysis of 5% of US Medicare population 1990-1999 (N = 1,091,201)
Foley. J Am Soc Nephrol. 2005;16:489. Slide credit: clinicaloptions.com
0
10
20
30
40
50
60
CHF AMI CVA/TIA PVD ASVD* Death
No diabetes/no CKD
Diabetes/no CKD
No diabetes/CKD
Diabetes/CKD

Patients
(%)
*Relative to diabetes alone.
15.7
32.3
29.5
T2D,
No CKD
No T2D,
CKD
T2D,
CKD
No T2D,
No CKD
10.3
Mortality Among Medicare Patients
Mortality Risk Doubles* in Comorbid T2D and CKD
 Retrospective analysis of US Medicare enrollees 1996-2000 (N = 1.1 million)
Collins. Kidney Int. 2003;64:S24. Slide credit: clinicaloptions.com
0
10
20
30
40

So…
Diabetes + CKD = CVD
Diabetes + CKD = Mortality
Detect Early
Treat Early

Definitions
Clinical syndrome
characterized by ↑ in
UAE, ↑ BP up to ESRD
with progressive rise in
CV risk.
The earliest evidence of
diabetic kidney disease
is the appearance of
albuminuria,
≥30mg/day

Natural History of
Diabetic Nephropathy:
Hyperglycemia Causes
Hyperfiltration, Followed
by Albuminuria and
Decreased GFR
Reference: Adapted from Friedman, 1999

And to be more precise…
*Kidney complications: anemia, bone and mineral metabolism, retinopathy, and neuropathy.
Alicic. CJASN. 2017;12:2032. Slide credit: clinicaloptions.com
Diagnosis
Yr 2 5 10 20 30
Hyperglycemia
Cellular injury Mesangial expansion glomerulosclerosis, tubulointerstitial fibrosis, and inflammation
Microalbuminuria Macroalbuminuria
GFR High Normal Low ESRD
Hypertension
Kidney complications*
Cardiovascular disease, infections, death

Mechanistic Links Between Prediabetes, Diabetes, DKD,
and End-Stage Kidney Disease
Prediabetes, Diabetes
Chronic hyperglycemia, metabolic syndrome, dyslipidemia, increased fatty acid metabolism
Hemodynamic
Inflammation
cytokines, chemokines
Oxidative stress
ROS
Apoptosis/autophagy
Mitochondrial dysfunction
mitophagy
Diabetic nephropathy
Extracellular matrix accumulation
Glomerular nodular sclerosis
Glomerular basement membrane thickening
Glomerular hyalinosis
podocytopathy
End-stage kidney
disease
Nicholas. NephSAP. 2020;19:110. Slide credit: clinicaloptions.com

Structural Changes in Diabetic Kidney Disease
Alicic. CJASN. 2017;12:2032. Reproduced with permission.
Normal Kidney Glomerulus Diabetic Kidney Glomerulus
Slide credit: clinicaloptions.com

Diabetic Glomerulopathy
Alicic. CJASN. 2017;12:2032. Reproduced with permission. Slide credit: clinicaloptions.com
Normal Glomerulus Diffuse mesangial expansion Nodularity, mesangiolysis
Kimmelstiel-Wilson nodules Dilated capillaries-
microaneurysms
Obsolescent glomerulus

Electron Microscope Images of Diabetic Glomerulopathy
Alicic. CJASN. 2017;12:2032. Reproduced with permission. Slide credit: clinicaloptions.com

KDIGO: Composite Ranking for Relative Risks by GFR
and Albuminuria
17
Levey. Kidney Int. 2011;80:17-28. Slide credit: clinicaloptions.com
Composite ranking for relative risks by
GFR and albuminuria (KDIGO 2009)
Albuminuria stages, description, and range (mg/g)
A1 A2 A3
Optimal and high-normal High Very high and nephrotic
<10 10-29 30-299 300-1999 ≥2000
eGFR
Stages,
Description,
and
Range
(ml/min/1.73m
2
)
G1 High and optimum
>105
90-104
G2 Mild
75-89
60-74
G3a Mild-moderate 45-59
G3b Moderate-severe 30-44
G4 Severe 15-29
G5 Kidney failure <15

So…
ACR ≥30 mg/gm and / or
eGFR <60
mL/min/1.73 m2
CKD in Diabetes means

https://doi.org/10.2337/dci22-0027

PERSONAL USE ONLY
Beware of Transient Albuminuria

What is the frequency of monitoring for
CKD in patients with diabetes?
At least annually, urinary
albumin (e.g., spot uACR)
and eGFR. B
Patients with diabetes and
uACR ≥300 mg/g and/or
eGFR 30–60 mL/min/m2
should be monitored twice
annually. B
Standards of Medical Care in Diabetes - 2022. Diabetes Care 2022;45(Suppl. 1):S144-S174

Case
• A 68-year-old man with >60 years of type 1 DM, no retinopathy and no history of
albuminuria is found to have 1.2 grams of proteinuria on routine check after
complaining of bodyache. His creatinine is 1.0 mg/dL. He is already on enalapril
and HCZ and his BP levels average 110/70. His A1C is 7%.
At this point you should
1. add valsartan
2. order CTUT
3. order UPEP, SPEP, ANA, CRP
4. Refer to nephrology

Be Aware of CKD of other causes

PERSONAL USE ONLY
Beware
of Other
Causes
of CKD
CKD, chronic kidney disease

PERSONAL USE ONLY
2018 Diabetes Canada CPG – Chapter 29. Chronic Kidney Disease in Diabetes
When to consider other causes of CKD
CKD, chronic kidney disease

Kidney
damage and
normal or  GFR
Kidney
damage and
mild 
GFR
Severe
 GFR
Kidney
failure
Moderate
 GFR
Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
Nephrologist
Primary Care Practitioner
The Patient (always)
and other subspecialists (as needed)
GFR 90 60 30 15
Who Should be Involved in the
Patient Safety Approach to CKD?
Patient safety
Consult?

When
to refer
https://doi.org/10.2337/dci22-0027
Patients should be referred for
evaluation by a nephrologist if
they have an estimated
glomerular filtration rate <30
mL/min/1.73 m2. A
Promptly refer to a nephrologist
for uncertainty about the etiology
of kidney disease, difficult
management issues, and rapidly
progressing kidney disease. A

CKD Patient Safety Issues
Fink JC, Brown J, Hsu, VD, et al. Am J Kidney Dis 2009;53:681-668.
Medication errors
• Toxicity (nephrologic
or other)
• Improper dosing
• Inadequate
monitoring
Electrolytes
• Hyperkalemia
• Hypoglycemia
• Hypermagnesemia
• Hyperphosphatemia
Miscellaneous
• Multidrug-resistant
infections
• Vessel
preservation/dialysis
access

CKD Patient Safety Issues (cont.)
Diagnostic tests
• Iodinated contrast media: AKI
• Gadolinium-based contrast: NSF
• Sodium Phosphate bowel
preparations: AKI, CKD
CVD
• Missed diagnosis
• Improper management
Fluid management
• Hypotension
• AKI
• CHF exacerbation
AKI = acute kidney injury; CHF = congestive heart failure; NSF = nephrogenic systemic fibrosis.
Fink JC, Brown J, Hsu, VD, et al. Am J Kidney Dis 2009;53:681-668..

Also, refer
early if…
Chronic, progressive loss of kidney function
ACR persistently >60 mg/mmol
eGFR <30 mL/min/1.73 m2
Unable to remain on renal-protective therapies due to
adverse effects such as hyperkalemia or a >30% increase in
serum Cr within 3 months of starting ACEi or ARB
Unable to achieve target BP (could be referred to any
specialist in hypertension)

Optimize
blood
glucose
• Optimize glucose control to reduce
the risk or slow the progression of
chronic kidney disease. A
Standards of Medical Care in Diabetes - 2022. Diabetes Care 2022;45(Suppl. 1):S144-S174

What are the
preferred
antidiabetic
drugs in patients
with CKD?

ADA. Diabetes Care. 2021;44:S1. Slide credit: clinicaloptions.com
COMPELLING NEED TO
MINIMIZE WEIGHT GAIN OR
PROMOTE WEIGHT LOSS
SGLT2i2
+HF
 Particularly
HFrEF
(LVEF <45%)
To avoid
therapeutic inertia
reassess and modify
treatment regularly
(3-6 months)
FIRST-LINE Therapy is Metformin and Comprehensive Lifestyle (including weight management and physical activity)
INDICATORS OF HIGH-RISK OR ESTABLISHED ASCVD, CKD, OR HF†
NO
CONSIDER INDEPENDENTLY OF BASELINE A1C OR
INDIVIDUALIZED A1C TARGET, OR METFORMIN USE*
+ASCVD/Indicators of High Risk
GLP-1 RA with
proven CVD
benefit1
If A1C above target
SGLT2i with proven
benefit in this
population5,6,7
COMPELLING NEED TO MINIMIZE
HYPOGLYCEMIA
DPP-4i GLP-1 RA SGLT2i TZD
If A1C
above target
If A1C
above target
If A1C
above target
If A1C
above target
SGLT2i
OR
TZD
SGLT2i
OR
TZD
GLP-1 RA
OR
DPP-4i
OR
TZD
SGLT2i
OR
DPP-4i
OR
GLP-1 RA
If A1C above target
GLP-1 RA with
good efficacy
for weight loss10
GLP-1 RA with
good efficacy for
weight loss8
SGLT2i
EITHER/OR
If A1C above target
COST IS A MAJOR ISSUE9-10
SU4 TZD12
TZD12 SU4
If A1C above target
If A1C above target
IF A1C ABOVE INDIVIDUALIZED TARGET PROCEED AS BELOW
 Established ASCVD
 Indicators of high ASCVD risk (age
≥55 years with coronary, carotid,
or lower extremity artery stenosis
>50%, or LVH
SGLT2i with
proven CVD
benefit1
Either/or
If further intensification is required
or patient is unable to tolerate GLP-
1 RA and/or SGLT2i choose agents
demonstrating CV benefit and/or
safety:
 For patients on a GLP-1 RA,
consider adding AGLT2i with
proven CVD benefit and vice
versa
 TZD2
 DPP-4i if not on GLP-1 RA
 Basal insulin3
 SU4
+CKD
PREFERABLY
SGLT2i with primary
evidence of reducing CKD
progression
OR
SGLT2i with evidence of
reducing CKD progression
in CVOTs5,6,8
OR
GLP-1 RA with proven CVD
benefit1 if SGLT2i not
tolerated or
contraindicated
DKD and Albuminuria6
For patients with T2D and CKD8
(e.g., eGFR <60 mL/min/1.73
m2) and thus at increased risk
of cardiovascular events
NO
GLP-1 RA with
proven CVD
benefit1
SGLT2i with
proven CVD
benefit1
Either/or
Continue with addition of other agents as outlined above
If A1C above target
Consider the addition of SU4 OR basal insulin:
 Choose later generation SU with lower risk of hypoglycemia
 Consider basal insulin with lower risk of hypoglycemia9
If A1C above target
Insulin therapy basal insulin
with lowest acquisition cost
OR
Consider other therapies
based on cost
If quadruple therapy required,
or SGLT2i and/or GLP-1 RA not
tolerated or contraindicated,
use regimen with lowest risk of
weight gain
PREFERABLY
DPP-4i (if not on GLP-1 RA)
based on weight neutrality
If DPP-4i not tolerated or
contraindicated or patient
already on GLP-1 RA,
cautious addition of:
▪ SU4 ▪ TZD2 ▪ Basal Insulin
ADA Clinical Practice Guidelines: Glucose-Lowering Medications in T2D

What are
issues to be
considered
while treating
CKD in
patients with
diabetes
In patients with chronic kidney disease
who have ≥300 mg/g urinary albumin, a
reduction of 30% or greater in mg/g
urinary albumin is recommended to slow
chronic kidney disease progression. B
Optimization of blood pressure control
and reduction in blood pressure
variability to reduce the risk or slow the
progression of chronic kidney disease is
recommended. A

Just
reduction of
albuminuria
is a success
Clinical Journal of the American Society of Nephrology. 2015 Jun 5;10(6):1079-88.

ACEi and ARBs
• In nonpregnant patients with diabetes and hypertension, either an ACEi
or an ARB is recommended for those with modestly elevated urinary
albumin-to-creatinine ratio (30–299 mg/g creatinine) B and is strongly
recommended for those with urinary albumin-to creatinine ratio ≥300
mg/g creatinine and/or estimated glomerular filtration rate <60
mL/min/1.73 m2. A
• Monitor serum creatinine and potassium levels for the development of
increased creatinine or changes in potassium when ACEi, ARBs, or
diuretics are used. B

Is ACEi + ARBs
combination is
recommended
?

What about primary prevention of CKD?
• An ACE inhibitor or an angiotensin receptor blocker is not
recommended for the primary prevention of chronic kidney
disease in patients with diabetes who have normal BP, normal
uACR (<30 mg/g), and normal eGFR. A

Quiz
52 Year old female, diabetes, hypertension, albuminuria
eGFR 55 ml/min
She was prescribed ramipril
2 weeks later, her cousin text you and tell you that the GFR is now 50
and he is concerned with the nephrotoxic effect of this group of drug?
ADA SoC 2022: Do not discontinue renin-angiotensin
system blockade for minor increases in serum creatinine
(<30%) in the absence of volume depletion. A
KDIGO Practice Point: Continue ACEi or ARB therapy
unless serum creatinine rises by >30% within 4 weeks
following initiation of treatment or an increase in dose.

Ann Intern Med. doi:10.7326/M20-5938

Residual Risk or unable to use SGLT2i
• In patients with chronic kidney disease who are at increased risk for
cardiovascular events or chronic kidney disease progression or are unable to use
a sodium–glucose cotransporter 2 inhibitor, a nonsteroidal mineralocorticoid
receptor antagonist (finerenone) is recommended to reduce chronic kidney
disease progression and cardiovascular events. A

Finerenone: Novel, Nonsteroidal, Selective
Mineralocorticoid Receptor Antagonist
1. Kolkhof. Handb Exp Pharmacol. 2017;243:271. 2. Kolkhof. J Cardiovasc Pharmacol. 2014;64:69. 3. Grune. Hypertension. 2018;71:599.
N
H
H2
N N
N
Bulky, nonsteroidal molecule1
Unique structure results in selective and potent interaction
with the MR and regulation of
gene expression1
Exhibits antifibrotic and anti-inflammatory effects2,3
Slide credit: clinicaloptions.com

Don’t ban everything
• For people with non-dialysis dependent stage 3
or higher chronic kidney disease, dietary protein
intake should be a maximum of 0.8 g/kg body
weight per day (the recommended daily
allowance). A
• For patients on dialysis, higher levels of dietary
protein intake should be considered, since
malnutrition is a major problem in some dialysis
patients. B

Don’t forget
Reference: De Zeeuw et al. Kidney Int 2004; 65(6):2309–2320.
Control
• Control blood pressure
Reduce
• Reduce sodium intake
Achieve
• Achieve good control of diabetes early; may help prevent albuminuria
Reduce
• Reduce weight, if obese
Achieve
• Achieve tobacco cessation

PERSONAL USE ONLY
If the patient
get sick,
what advice
you offer
him?

65–year–old man with T2D for 25 years and
Retinopathy
He may have diabetic
kidney disease: he has
long term diabetes, and
both retinopathy and
albuminuria.

69–year–old Woman with DM 2 for 15 years,
without Retinopathy, Lupus for 4 years
Probably not, she has
normal urine albumin
and no retinopathy.

Metformin recommendations for patients
with T2D and CKD from ADA and KDIGO
ADA SoC 2022
• First-line therapy depends on
comorbidities, patient-centered
treatment factors, and
management needs and
generally includes metformin
and comprehensive lifestyle
modification (A).
KDIGO
• We recommend treating
patients with T2D, CKD, and an
eGFR >30 mL/min/m2 with
metformin (1B).
• Adjust the dose of metformin
when the eGFR is <45
mL/min/m2, and for some
patients when the eGFR is 45–59
mL/min/m2.

GLP1A recommendations for patients with
T2D and CKD from ADA and KDIGO
ADA SoC 2022
• Among patients with T2D who
have established ASCVD or
established kidney disease, an
SGLT2i or GLP-1 receptor agonist
with demonstrated CVD benefit
is recommended as part of the
comprehensive CV risk reduction
and/or glucose-lowering
regimens (A).
KDIGO
• In patients with T2D and CKD
who have not achieved
individualized glycemic targets
despite use of metformin and
SGLT2i treatment, or who are
unable to use those
medications, we recommend a
long-acting GLP-1 receptor
agonist (1B).

SGLT2i
recommendations
for patients with
T2D and CKD from
KDIGO
• An SGLT2i with proven kidney or
cardiovascular benefit is recommended for
patients with T2D, CKD, and eGFR >20
mL/min/1.73 m2. Once initiated, the SGLT2i
can be continued at lower levels of eGFR.

Considerations for selecting glucose-lowering agents in patients with T2D and CKD

CKD and Diabetes: Tips & Tricks

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