Challenges in Diagnosis and Management of Diabetic Kidney Disease - Dr. Gawad

Challenges in Diagnosis and
Management of Diabetic Kidney
Disease
Mohammed Abdel Gawad
Nephrology Specialist
Kidney & Urology Center (KUC)
Alexandria – EGY
drgawad@gmail.com
14th Damanhour Nephrology Annual Conference
13/Nov/2014

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drgawad@gmail.com

Diabetic Kidney Disease
Diagnosis Management

Diagnosis

IMPORTANT MESSAGE
Hematuria Proteinuria Rising creatinine
• Renal problems in diabetic patients are NOT
ALWAYS due to diabetic nephropathy and
even it may not be due to DM.

Renal & Urological Problems that may
be presented in Diabetics
Papillary necrosis
- Ischemic nephropathy
- Renal artery stenosis
- Drug induced
- Other ppt factors for AKI
Diabetic glomerulopathy
(diabetic nephropathy)
Autonomic neuropathy of the
bladder
UTI
Any other glomerular disease
not related to DM

Renal & Urological Problems that may
be presented in Diabetics
Papillary necrosis
Always ask yourself: Is it DN?
When to suspect other cause rather than DN?
- Drug induced
bladder
UTI
not related to DM
When to biopsy?

Is it Diabetic Nephropathy?
You have to answer the following
1. What is the type of DM?
2. Is there an evidence of Diabetic retinopathy?
3. Proteinuria:
a. Is the evolution of proteinuria is typical (micro then macro)?
b. Is the range of proteinuria coincides with DN stage?
c. What is the rate of proteinuria progression?
4. Hematuria: Is it microscopic or macroscopic?
5. Rising Cr and decreasing GFR:
a. Is it related to proteinuria?
b. What is the rate of renal impairment progression?
6. Hypertension: refractory or not?
7. What is the drug history?
8. Is there any ppt factor for AKI?

Diabetic Nephropathy & Diabetic Retinopathy
Type 1 DM
Mogensen CE. Diabetes. 1997;56(Suppl 2):104-111.

Type 1 DM
Pre
(1 &2)
5y 15y 25y
Incipient (3)
(microalbuminuria
& HTN)
Overt (4)
(proteinuria,
nephrotic syndrome
and decreasing GFR)
ESRD (5)
At 5 years from onset of DM type 1,
nephropathy coincides with
retinopathy
So if nephropathy is evident in absence
of retinopathy in Type 1 DM
Search for other cause of
nephropathy rather that DM ±
Renal Biopsy
(especially if there is S&S of
other systemic disease)
Diabetic retinopathy is present in virtually
all patients with type 1 diabetes and
nephropathy *
* Girach A, Vignati L. Diabetic microvascular complications. J Diabetes Complications. 2006;20:228-237.

Type 2 DM Only 50% to 60% of proteinuric
patients with type 2 diabetes
suffer from retinopathy. **
Consequently, the absence of
retinopathy does not exclude
the diagnosis of DN in patients
with type 2 diabetes.
*
In type 2 DM the prevalence of
nondiabetic renal disease could
vary from 12 to 38% ***
* GIUSEPPE REMUZZI et al. N Engl J Med, Vol. 346, No. 15· April 11, 2002
** Wolf G, Müller N, Mandecka A, Müller UA. Clin Nephrol. 2007;68:81-86.
*** Huang F et al. Clin ephrol 2007, 67: 293-297.
**** Pham TT et al. Am J Nephrol. 2007;27:322-328.

Type 2 DM
± Renal
Biopsy
Only 50% to 60% of proteinuric
patients with type 2 diabetes
suffer from retinopathy. **
Consequently, the absence of
retinopathy does not exclude
the diagnosis of DN in patients
with type 2 diabetes.
*
In type 2 DM the prevalence of
nondiabetic renal disease could
vary from 12 to 38% ***
When to suspect other
cause****?
1- Younger patients with DM
2- Short duration of DM
3- Atypical presentation (atypical
proteinuria or hematuria, rapid rising
Cr ….. etc) or other ppt factors
(discussed later)
When to
suspect other
cause?
* GIUSEPPE REMUZZI et al. N Engl J Med, Vol. 346, No. 15· April 11, 2002
** Wolf G, Müller N, Mandecka A, Müller UA. Clin Nephrol. 2007;68:81-86.
*** Huang F et al. Clin ephrol 2007, 67: 293-297.
**** Pham TT et al. Am J Nephrol. 2007;27:322-328.

Diabetic Nephropathy & Proteinuria
Pre
(1 &2)
5y 15y 25y
Incipient (3)
(microalbuminuria
& HTN)
Overt (4)
(proteinuria,
nephrotic syndrome
and decreasing GFR)
ESRD (5)
If evolution of
proteinuria is atypical:
development of overt
proteinuria without
previous
microalbuminuria.
Search for other cause of nephropathy
rather that DM ± Renal Biopsy
(especially if there is S&S of other
systemic disease)
Costacou T, et al. Am J Kidney
Dis. 2007;50(5):721

Pre
(1 &2)
5y 15y 25y
Incipient (3)
(microalbuminuria
& HTN)
Overt (4)
(proteinuria,
nephrotic syndrome
and decreasing GFR)
ESRD (5)
If evolution of
proteinuria without
previous
microalbuminuria.
systemic disease)
Rate of proteinuria
progression is slow
If the onset of
proteinuria has
been sudden and
rapid
Dis. 2007;50(5):721

Pre
(1 &2)
5y 15y 25y
Incipient (3)
(microalbuminuria
& HTN)
Overt (4)
(proteinuria,
nephrotic syndrome
and decreasing GFR)
ESRD (5)
If evolution of
proteinuria without
previous
microalbuminuria.
systemic disease)
If the onset of
proteinuria has
been sudden and
rapid
10-15 years
Overt proteinuria
in diabetes type 1
for <10 years
Rate of proteinuria
progression is slow
Dis. 2007;50(5):721

DN without Albuminuria
Ischemic Nephropathy – Type 2 DM
Papillary necrosis
- Drug induced
bladder
UTI
not related to DM

HYPERperfusion/
Hyperfiltration
↑
Angiotensin II
Intraglomerular
Pressure
Hyperglycemia
Proteinuria
↓
Intraglomerular
Pressure
Atherosclerosis
J Am Soc Nephrol. 2003;14:3217-3232

HYPERperfusion/
Hyperfiltration
↑
Angiotensin II
Intraglomerular
Pressure
Hyperglycemia
Proteinuria
HYPOperfusion/
Ischemia
↓
Intraglomerular
Pressure
Atherosclerosis

DN without Albuminuria
Ischemic Nephropathy – Type 2 DM
• Renal ultrasound reveals small kidneys.
• Raised Serum Cr after administration of ACE-i
• Without albuminuria
Jamine P. Dwyer et al. DEMAND study. Cardiorenal Med, 2012;2:1-10

Jamine P. Dwyer et al. DEMAND study. Cardiorenal Med, 2012;2:1-10

DN without Albuminuria - Type 1 DM
• MARK E. MOLITCH. Diabetes Care 33:1536–1543, 2010
•Also same results are reported in:
•Caramori ML et al. Diabetes 52:1036-1040, 2003.
•Lane PH et al. Diabetes 41:581-586, 1992
•MacIsaac RJ et al. Diabetes Care 27:195-200,2004

Diabetic Nephropathy & Hematuria
Is it Micro or Macroscopic?
Hematuira in diabetic patient
Microscopic
hematuria is seen in
66% of patients with
DN *
Macroscopic hematuria
±
active nephritic urinary sediment
(acanthocytes and red cell casts)
(especially if there is S&S of other systemic
disease)
Red blood cell casts have
also been described in
patients with diabetic
* Akimoto T, Ito C, Saito O, et al. Nephron Clin Pract. 2008; 109:c119-c126.
** Chong YB et al. Ren Fail. 2012;34(3):323-8. Epub 2012 Jan 17.
nephropathy **

Diabetic Nephropathy & Renal Impairment
Pre
(1 &2)
5y 15y 25y
Incipient (3)
(microalbuminuria
& HTN)
Overt (4)
(proteinuria,
nephrotic syndrome
and decreasing GFR)
ESRD (5)
If renal impairment is rapid
Search for other cause
Rate of renal
impairment
progression is slow
first, of course, renovascular
disease must be excluded
other cause of nephropathy

Diabetic Nephropathy & Renal Impairment
Pre
(1 &2)
5y 15y 25y
Incipient (3)
(microalbuminuria
& HTN)
Overt (4)
(proteinuria,
nephrotic syndrome
and decreasing GFR)
ESRD (5)
Significant proteinuria without/with
non coinciding renal impairment
If renal impairment is rapid
Search for other cause
Rate of renal
impairment
progression is slow
first, of course, renovascular
disease must be excluded
other cause of nephropathy

Diabetic Nephropathy & Refractory HTN
Refractory hypertension (and fluid
retention) in diabetic patients is highly
suggestive for renovascular disease

Diabetic Nephropathy & Drugs
ACEi & ARBs
> 30% reduction in GFR
within 2-3 months after
initiation
Suspect renovascular
disease

Diabetic Nephropathy & Drugs
Diabetics kidneys are at
high risk to be affected
by nephrotoxic drugs
NSAIDs Contrast
Any other nephrotoxic
drug

ppt factors for AKI in Diabetics
They are the same as any high risk population
1. Dehydration (fluid loss, hyperglycemia, decrease fluid
intake).
2. UTI.
3. Drugs.
4. Cardiac problem.
5. Septicemia.
6. Surgery.

To Conclude
When to suspect other Cause(s) of Renal
Disease rather than DN? (Is it DN?) – Step 1
Step 1:
Renal US
Evidence of
chronic
changes
No need for
biopsy
No evidence
of chronic
changes
Go to Step 2
Overall, renal biopsy is indicated only in a
small minority of diabetic patients.

To Conclude
When to suspect other Cause(s) of Renal Disease
rather than DN? (Is it DN?) – Step 2
Suspect other cause rather that DN if:
Diabetic retinopathy - Absent in Type 1
- Absent in type 2 +
1- Short duration of DM
2- Atypical presentation or other ppt factors
Proteinuria & Nephrotic syndrome
(Don’t forget DN without
albuminuria)
- Development of overt proteinuria without previous microalbuminuria
- Overt proteinuria in diabetes type 1 for <10 years
- If the onset of proteinuria has been sudden and rapid
- Resistant Nephrotic Syndrome
Hematuria Macroscopic hematuria & active urinary sediment
(Don’t forget casts are described in DN also)
Rising Cr and decreasing GFR - If renal impairment is rapid
- If significant proteinuria without renal impairment
Hypertension Refractory HTN
Drug history - ACEi & ARBs: > 30% reduction in GFR within 2-3 months after initiation
- NSAIDs & Contrast
- Others
ppt factor for AKI Dehydration, UTI, Drugs, Cardiac problem, Septicemia, Surgery.
Systemic disease S&S of other systemic disease
Red and green colored indications are not listed in KDOQI Guidelines for Diabetes & CKD

Pathology
Pathology - Nodular
Kimmelstiel Wilson nodules
Pathognomonic for diabetes
But reported in only 10% to 50% of
biopsy specimens in both type 1
and type 2 diabetes.

Pathology
Pathology - Nodular Pathology - Diffuse
Kimmelstiel Wilson nodules - MORE FREQUENT than the nodular lesion
- Correlates with the clinical manifestations
of worsening renal function

Pathology
DN
Other
Pathology
DN
+ Other Pathology
LM/IF/EM whenever possible,
especially if there is high suspicion of other pathology

Management
Glycemic
Control
Hypertension
Other Strategies
Proteinuria &
Progression
Aldosterone
Breakthrough
Emerging Therapy

Management
Glycemic
Control

DCCT/EDIC Research Group. N Engl J Med. 2011;365:2366-2376.

Primary outcome was a composite of nonfatal myocardial
infarction, nonfatal stroke, or death from cardiovascular causes
ACCORD Group. N Engl J Med. 2008;358:2545-2559.

22% increase in mortality from any cause and
did not significantly reduce major CV events
Primary outcome was a composite of nonfatal myocardial
infarction, nonfatal stroke, or death from cardiovascular causes
ACCORD Group. N Engl J Med. 2008;358:2545-2559.

Glycemic Control
HbA1c% Target
INDIVIDUALIZED

Management
Hypertension
BP Target?
Which Class?
ACE-i/ARBS fit for all?
ACE-I + ARBS?

There was also a trend for increased adverse cardiovascular
outcomes, including all-cause mortality, with diastolic blood
pressures below 85 mmHg
Pohl MA et al. J Am Soc Nephrol. 2005;16:3027-3037.

Cushman WC et al. N Engl J Med. 2010;362:1575-1585.

Which Anti-HTN Class?
• The overall effect of BP lowering may be more important than
the type of antihypertensive used.
• Antihypertensive therapies, regardless of agent used:
– reduce UAE
– delay progression of nephropathy
– improve survival in both type 1 and type 2 diabetic patients with DN
Ismail N et al. Kidney Int. 1999;55:1-28.
Mogensen CE. J Intern Med. 2003;254:45-66.
• RAS blockade with ACE inhibitors or ARBs confers preferential
renoprotection that is independent of BP reduction.
Microalbuminuria Captopril Study Group. Diabetologia. 1996;39:587-593.
EUCLID Study Group. Lancet. 1997;349:1787-1792.
Ann Intern Med. 2001;134:370-379.
Lewis EJ et al. N Engl J Med. 1993;329:1456-1462.
Parving HH et al. N Engl J Med. 2001;345:870-878.
Viberti G, Wheeldon NM. Circulation. 2002;106:672-678.
Brenner BM et al. N Engl J Med. 2001;345:861-869.
Lewis EJ et al. N Engl J Med. 2001;345:851-860.
Barnett AH et al. N Engl J Med. 2004;351:1952-1961.

ACE-i / ARBs Renoprotection in DN
HYPERperfusion/
Hyperfiltration
↑
Angiotensin II
Intraglomerular
Pressure
Hyperglycemia
Proteinuria
J Am Soc Nephrol. 2003;14:3217-3232

ACE-i / ARBs Renoprotection in DN
HYPERperfusion/
Hyperfiltration
Hyperglycemia Angiotensin II
ACE-I
& ARBs
↓
Intraglomerular
Pressure
J Am Soc Nephrol. 2003;14:3217-3232

Renal Response to ACE-i
Serum creatinine concentration may increase up
to 30% after an ACE inhibitor is started.
This rise in creatinine is associated with
long-term renoprotection
ACE inhibitor should not necessarily be
stopped in these patients
Bakris GL et al. Arch Intern Med.2000;160:685-693.

Enhance ACE-i/ARBs Action
The antiproteinuric effect of RAS
blockade is enhanced by
low-sodium diet
(<2 g/day)
combination of a loop diuretic
or a thiazide diuretic

ACE-i / ARBs in DN
HYPERperfusion/
Hyperfiltration
HYPOperfusion/
Ischemia
↓
Intraglomerular
Pressure
Atherosclerosis
ACE-I
& ARBs
↓
Intraglomerular
Pressure

ACE-i / ARBs in DN
HYPERperfusion/
Hyperfiltration
HYPOperfusion/
Ischemia
Atherosclerosis
ACE-I
& ARBs
↓
Intraglomerular
Pressure
Angiotensin II
↑
Intraglomerular
Pressure
Important Auto-regulatory
mechanism to maintain GFR
ACE-I & ARBs are
dangerous in this case

ONTARGET Investigators. N Engl J Med. 2008;358:1547-1559.

VA NEPHRON-D Investigators. N Engl J Med. 2013;369:1892-1903.

The VA NEPHRON-D study was in fact terminated
early because of the unfavorable patient-risk
benefit ratio.
VA NEPHRON-D Investigators. N Engl J Med. 2013;369:1892-1903.

Management
Other Strategies

Smoking cessation
Dieting
Weight reduction
N Engl J Med 2008;358:580-91.
Phisitkul K et al. Am J Kidney Dis. 2003;41:319-327.
Ritz E et al. Metab. 2000;26(suppl 4):54-63.

Management
Proteinuria &
Progression

Relation between Proteinuria and
disease progression in DN
Patients who progressed to
severely increased albuminuria
had the highest rate of loss of
GFR
J Am Soc Nephrol. 2003;14:3217-3232
Perkins BA et al. Kidney Int. 2010;77(1):57.
Caramori ML, Fioretto P, Mauer M. Diabetes. 2003;52(4):1036.
MacIsaac RJ et al. Diabetes Care. 2006;29(7):1560.
Perkins BA et al. J Am Soc Nephrol. 2007;18(4):1353.

Relation between Proteinuria and
disease progression in DN
The degree of albuminuria is not
always necessarily linked to disease
progression in patients with diabetic
nephropathy
Some patients may progress to
advanced disease although these
patients had either stable
moderately increased albuminuria
or regression to normal albuminuria.
Patients who progressed to
severely increased albuminuria
had the highest rate of loss of
GFR
The rate of loss of GFR was
lower in patients with
regression to normal
albuminuria compared with
patients with stable moderately
increased albuminuria
Perkins BA et al. Kidney Int. 2010;77(1):57.
Caramori ML, Fioretto P, Mauer M. Diabetes. 2003;52(4):1036.
MacIsaac RJ et al. Diabetes Care. 2006;29(7):1560.
Perkins BA et al. J Am Soc Nephrol. 2007;18(4):1353.

Management
Aldosterone
Breakthrough

Aldosterone Breakthrough
Screening for aldosterone
breakthrough
(evidence is not strong enough to
support screening)
Hollenberg NK. Kidney Int. 2004;66:1-9.
Microalbuminuria Captopril Study Group. Diabetologia. 1996;39:587-593.
79
In a subset of patients despite
ACE inhibitor and ARB therapy
Plasma aldosterone levels are
elevated (aldosterone
breakthrough)
Aldosterone promotes tissue
inflammation and fibrosis with
faster decline in GFR
Aldosterone blockade with close
monitoring of serum potassium levels may
represent optimal therapy for patients
who show aldosterone breakthrough
during treatment with an ACE inhibitor or
an ARB and who no longer show maximal
antiproteinuric effects with these agents

Management
Emerging Therapy

Management Home Messages
• HbA1C% should be individualized
• Lower BP target (< 120mmHg) increases mortality
• The overall effect of BP lowering may be more important than the type of
antihypertensive used
• RAS blockade with ACE inhibitors or ARBs confers preferential
renoprotection that is independent of BP reduction.
• Take care of ACE-i/ARBs with ischemic nephropathy
• Don’t combine ACE-I with ARBs
• Multitarget treatment is mandatory (diet, weight loss, smoking …etc)

Thank You
Mohammed Abdel Gawad
(drgawad@gmail.com)

Challenges in Diagnosis and Management of Diabetic Kidney Disease - Dr. Gawad

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