1. Diabetic Nephropathy
new horizon
Dr. Muhamed Al Rohani,MD

2. Definition
Classical definition: progressive rise in urine albumin
excretion coupled with increasing BP and leading
to declining GFR and CKD
Abnormal urine albumin excretion
• >30 mg/24 hours
and/or
diabetic glomerular lesions
and/or
loss of glomerular filtration rate
ADA recommendations, Diabetes Care, January 2012

3. Prevalence Incidence

4. Epidemiology
Increase prevalence of DM
India china USA
4% 1995 – 5.4% 2025
Worldwide:
2.8 % 171 million 2000 –
4.4% 366 million 2030
Now: USA 7% (20.8 million) off
population has DM
DN prevalence
In India: 5.5% and 8.9%
Asian Indians in UK 22.3%
Increased mortality rate
With protinuria
Without proteinuria
Increased CV events

5. Harris MI. Clin Invest Med. 1995;18:231-239.
Nelson RG, et al. Adv Nephrol Necker Hosp. 1995;24:145-156.
World Health Organization. Diabetes Mellitus Fact Sheet 138. 2002.
ADA. National diabetes fact sheet. Available at:
http://www.diabetes.org/diabetes-statistics/national-diabetes-fact-sheet.jsp.
Microvascular Complications Macrovascular Complications
Complications of Type 2 Diabetes
Affect Every Part of the Body
Peripheral
Vascular Disease
Heart
Disease
Diabetic Retinopathy
Leading cause of
blindness in
working-age adults
Diabetic Nephropathy
Leading cause of
end-stage renal disease
Diabetic Neuropathy
Leading cause of
nontraumatic lower
extremity amputations
Stroke
2- to 4-fold increase
in cardiovascular
mortality and stroke

6. Specific Infections
• Community acquired
pneumonia
• Acute bacterial cystitis
• Acute pyelonephritis
• Emphysematous
pyelonephritis
• Perinephric abscess
• Fungal cystitis
• Necrotizing fasciitis
• Invasive otitis externa
• Rhinocerebral
mucormycosis
• Emphysematous
cholecystitis

7. Natural history of DN

10. Type I
Duration:
Microalbuminuria after 20 yrs in 20 –
30 % of DM patients
ESRD after 10 yrs,
Type 2
Duration:
CKD or ESRD in 1% of pts in the time of
diagnosis
ESRD in 20 -30 % at 20 yrs.
Poor glycemic control
Strict control reduce and slow the risk of microvascular and even
macrovascular complications.
Hypertension:
Cause of and results of diabetic renal disease
In DM1 5% in 10 yrs
33% in 20 yrs
70% in 40 yrs
Rise with 3 yrs of microalbuminuria with Incidence of 15 – 25%
75 – 85% in all diabetic nephropathy

15. Effect of Increased Glomerular Permeability to Proteins on Progressive Renal Injury.
Remuzzi G, Bertani T. N Engl J Med 1998;339:1448-1456.
Gilbert RE, Marsden PA. N Engl J Med 2008;358:1628-1630.

17. Flow chart for classifying DN.
Tervaert T W C et al. JASN©2010 by American Society of Nephrology

21. Representative examples of the morphologic
lesions in DN. (A) Glomerulus showing only mild
ischemic changes, with splitting of Bowman's
capsule.
©2010 by American Society of Nephrology

22. Pathological classification of DN
Class Description Inclusion Criteria
I
Mild or nonspecific LM changes and
EM-proven GBM thickening
Biopsy does not meet any of the criteria mentioned below
for class II, III, or IV
GBM > 395 nm in female and >430 nm in male individuals
9 years of age and oldera
IIa
Mild mesangial expansion
Biopsy does not meet criteria for class III or IV
Mild mesangial expansion in >25% of the observed
mesangium
IIb
Severe mesangial expansion
Biopsy does not meet criteria for class III or IV
Severe mesangial expansion in >25% of the observed
mesangium
III Nodular sclerosis (Kimmelstiel–
Wilson lesion)
Biopsy does not meet criteria for class IV
At least one convincing Kimmelstiel–Wilson lesion
IV Advanced diabetic
glomerulosclerosis
Global glomerular sclerosis in >50% of glomeruli
Lesions from classes I through III

23. Treatment of Diabetic Nephropathy
Hypertension Control - Goal:
• lower blood pressure to <130/80 mmHg
– Antihypertensive agents
• Angiotensin-converting enzyme (ACE) inhibitors
– captopril, enalapril, lisinopril, benazepril, fosinopril, ramipril, quinapril,
perindopril, trandolapril, moexipril
• Angiotensin receptor blocker (ARB) therapy
– candesartan cilexetil, irbesartan, losartan potassium, telmisartan, valsartan,
esprosartan
• Aldestrone blockers; spirolactone and eplerenone

24. Table 2. Recommendations for the Comprehensive
Management of T2DM Patients with CKD
Factor Recommendations
Lifestyle factors Advice concerning smoking, diet, exercise, and alcohol intake
Blood glucose Treatment goal:
HbA1c <7.0%
Preprandial plasma glucose 90-130 mg/dl
Postprandial plasma glucose <180 mg/dl
Blood pressure Goal ≤130/80 mm Hg
Use maximal tolerated dose of ACE inhibitor or ARB before
adding a second agent
Cholesterol Goal <4.0 mmol/L for total cholesterol and <2.0 mmol/L for
LDL-C
Consider use of a statin irrespective of baseline lipid values for
the secondary prevention of cardiovascular disease
Platelets Consider use of low dose aspirin for the secondary prevention
of cardiovascular disease
Monitoring Annual monitoring of eGFR and ACR

25. Criteria for the Diagnosis of Diabetes
A1C ≥6.5%
OR
Fasting plasma glucose (FPG)
≥126 mg/dL (7.0 mmol/L)
Ono caloric intake for at least 8h
2-h plasma glucose ≥200 mg/dL
(11.1 mmol/L) during an OGTT
OR
A random plasma glucose ≥200 mg/dL (11.1 mmol/L)
ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S12. Table 2.
A1c Target :
Intensive / conventional
Outcome
UKPDS
10 yrs
7% / 7.9% Significant reduction of microvascualr
comp. in intensive group
ADVANCE
5 yrs
6.5% / 7.3% Reduction of macro and micro vascuar
and meanly nephropathy
ACCORD <6% / 7- 7.9% Stopped because of increased
incidence of hypoglycemic evets

26. Prediabetes: IFG, IGT, Increased A1C
Categories of increased risk for diabetes (prediabetes)*
FPG 100–125 mg/dL (5.6–6.9 mmol/L): IFG
OR
2-h plasma glucose in the 75-g OGTT
140–199 mg/dL (7.8–11.0 mmol/L): IGT
OR
A1C 5.7–6.4%
*For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately greater at
higher ends of the range.
ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S13. Table 3.
Category Spot collection (µg/mg
creatinine)
Normal <30
Microalbuminuria 30-299
Macroalbuminuria (clinical) ≥300

27. Recommendations: Nephropathy
• To reduce risk or slow the progression of nephropathy
– Optimize glucose control (A)
– Optimize blood pressure control (A)
ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S34.
• Assess urine albumin excretion annually
– In type 1 diabetic patients with diabetes duration of ≥5 years
– In all type 2 diabetic patients at diagnosis
• Measure serum creatinine at least annually
– In all adults with diabetes regardless of degree of urine albumin
excretion
– Serum creatinine should be used to estimate GFR and stage
level of chronic kidney disease, if present

28. The therapeutic strategies for DKD are limited due to several
factors:
– Lack of screening for DKD,
– Lack of implementation of optimal standard therapy for DKD,
– Current therapies primarily slow down, but do not halt the
progression of DKD.
These therapies include:
1. blood pressure, RAS blockers
2. lipid, glycemic, and weight control;
3. diet and lifestyle modifications;
4. antiplatelet aggregation therapy;
Statins have been shown to have
1. multiple antioxidant properties and improve vascular
remodeling (Briones et al., 2009).
2. shown to reduce proteinuria (Nakamura et al., 2005)
3. Shown to reduce the progression of DKD (Agarwal, 2007).

29. ACE inhibitors Trail
Heart Outcome Prevention Trail
Captopril Prevention Trail
Fosinopril versus Amliodepine Cardiovascular Events Trail
Appropriate BP Control Diabetes Trail
UK prospective Diabetes Study
Diabetes Exposed to Telmisartan And EnalapriIL Trail
BENEDICT TRAIL

30. ACE Inhibitors can prevent progression of renal
failure
120
160
200
240
280
320
350
400
80
0 1 2 3 4 5 6
Years
Ann Intern Med 118 577-581.1993
J Am Soc Nephrol 2006
Placebo
Enalapril 85
90
95
100
105
110
80
0 1 2 3 4 5 6
Years
Placebo
Enalapril
Normotensive Type 2 Diabetics
Proteinuria
(mg/day)
% Initial GFR
Risk reduction is 51%
Reduce microalbuminuria
All causes of mortality

31. Ruggenenti P et al. N Engl J Med 2004;351:1941-1951.
Conclusions
In subjects with type 2 DM and HTN but with
normoalbuminuria, the use of trandolapril plus
verapamil and trandolapril alone decreased
the incidence of microalbuminuria to a similar
extent. The effect of verapamil alone was
similar to that of placebo.

32. Olmesartan for the Delay or Prevention of Microalbuminuria
in Type 2 Diabetes
• 4447 patients to receive olmesartan 40 mg once daily or placebo
for a median of 3.2 years.
• BP <130/80 mm Hg.
• The primary outcome was the time to the first
• onset of microalbuminuria.
• The times to the onset of renal and CV events were analyzed as
secondary end points.
Conclusion:
• Olmesartan was associated with a delayed onset of
microalbuminuria, even though blood-pressure control
• The higher rate of fatal cardiovascular events with olmesartan
among patients withpreexisting coronary heart disease is of
concern.

33. Incidence of Progression to Diabetic Nephropathy during Treatment with 150 mg
of Irbesartan Daily, 300 mg of Irbesartan Daily, or Placebo in Hypertensive
Patients with Type 2 Diabetes and Persistent Microalbuminuria.
Parving H et al. N Engl J Med 2001;345:870-878.

34. Bardoxolyne methyl, has been shown to significantly improve the creatinine GFR and
cystatin C GFR in patients with DKD after only 4 weeks
(Schwartz, Denham, Hurwitz, Meyer, & Pergola, 2009).
Recent landmark phase 2 trial of 227 adults with CKD and type 2 DM demonstrated
that bardoxolone methyl ( 75 mg is the optimal dose) improved GFR by at least
8.2 +/-1.5 ml/min over placebo after 24 weeks of treatment and that this effect
was maintained after a year of therapy.
(Pergola, et al., 2011).
Bardoxolone methyl did not improve urinary albumin excretion.
In 3 phase BEACON study in CKD 4 stage disappointing results
PIRFENIDONE:
Antifibrotic (reduction of: ECM deposition, fibrogenic growth factor, fibroblast
proliferation)
Anti-inflammatory (reducation of: inflam. Cytokinase and inflam.cell accumulation
Antioxidant reduction of: markers of oxid. Stress, and its response.
Paricalcitol
Ruboxistaurtin
Allopurinol

35. Metformin in Patients with T2DM and CKD
 first-line treatment
 weight neutral,
 inexpensive,
 Low ris of hypoglycemia
 inhibits the generation of glucose in the liver.
 excreted unchanged by the kidney
• The recommendation from NICE in England and Wales,[24] and supported
by the ADA/EASD position paper,[8] is that metformin can be used
– down to an eGFR of 30 mL/min/1.73 m2,
– the dose of metformin should be reduced when eGFR is less than 45
mL/min/1.73 m2.
– Kidney function should be checked regularly (every 6 months)
– discontinued if eGFR falls below 30 mL/min/1.73 m2.
– prescribed with caution in patients with an eGFR less than 45 mL/min/1.73
m2, which is rapidly deteriorating.[22,24]
– All patients should be warned that if they develop a condition that can lead to
dehydration.
• Contradictory to guidance from NICE, the Study of Treatment and
Prevalence of Renal Disease in UK Diabetes Mellitus

36. Keys of diabetic nephropathy
Glomerulus:
Increased intraglomerular hypertension
Loss of neg. charged glycosaminoglycans in GBM
Increased GBM pore size
Podocyte changes and damages
Pathological abnormalities:
Thickening of GBM
Accumulation of mesangial matrix
Increase numbers of mesangial cells
Tubular part:
Thickening of TBM
Tubular atrophy
Interstitial fibrosis
Arteriosclerosis
Hypoglycemia as glucose toxicity.
Glycation and formation of advanced glycation
products
Increased flux through the polyol and
hexosamine pathways
Oxidative stress
Fibrotic changes seen in mesangium and
interstitium caused by
• Transforming growth factor B-1
• Connective tissue growth factor
Glomerular hyperfiltration and hypertrophy due
to:
• Growth fator
• Insulin-like growth factor -1
Vascular endothelial growth factor synthesised
by the podocyte maintains the fenestrae in
glom. endothelial cells, its cause constriction
of the efferent glomerular arteriole,
angiotensin II increases glomerular capillary
permeability to proteins stimulate mesangial
cell proliferation and accumulation of
mesangial matrix

38. Anti-DM drugs in CKD
Believed to be safe Gliplzide
Repaglidine
Glitazones
Linagliptin
Modifying dose Insulin
DDP-4 I
Sita
Vilda
Saxa
C/I metformin
Glebincamide
Glimepride
nataglinide

39. Poor food intake
Insufficient exercise
Uraemia –induced anorexia
Insulin metabolism disorder
Insulin resistance
Reduced insulin clearance
Inadequate drug therapy
Fluctuation of blood glucose and monitoring of glycemia
Recommended diabetes targets :
A1C
The Renal Association 2011 7.5%
Joint British societies 2005 6.5%
NICE 2011 6.5 – 7.5 % (individualize)

40. Indication of pancreas transplantation
Pancreas alone Pancreas after kidney Both K and P
- Low C peptide
- Rapid progressive diab.
Complications
- Low C peptide
- successful KT
- GFR > 40 ml/min/1.7 m2
-Low C peptide
- advance nephropahy
- GFR < 20 ml/min/1.7 m2

43. Avoid too many pain medications
Drink plenty of water
Prevention urinary tract infections
Correlated with Prevention Kidney Disease:
Healthy body weight
Exercise (30 min/day: improve diabetic control,
BP control, and heart function,body weight).
9. Normal blood lipid levels
Slowing & preventing Kidney Disease

45. Pathogenesis
Abnormalities of
vasodilatation

48. Risk factors:
Common risk factors:
Greater duration of DM
Metabolic syndrome
HTN
Hyperlipidemia
Cholesterol
LDL
Triglycerides
Poor DM control
Smoking
Obesity
Higher waist circumference
Lower adiponectin
Higher CRP
Albuminuria
CVD
Mortality
GFR < 60ml/min/1.73m2

49. Hyperglycemia
Increased
glucagon
secretion
Decreased
insulin
secretion
Increased
lipolysis
Decreased
glucose uptake
Muscles
Increased
glucose
reabsorption
Kidney
Increased HGP
Neurotransmitter
Dysfunction

50. Criteria for Testing for Diabetes in Asymptomatic
Adult Individuals (1)
• Physical inactivity
• First-degree relative with diabetes
• Women who delivered a baby
weighing >9 lb or were diagnosed
with GDM
• Hypertension (≥140/90 mmHg or on
therapy for hypertension)
• HDL cholesterol level
<35 mg/dL (0.90 mmol/L) and/or a
triglyceride level >250 mg/dL (2.82
mmol/L)
• Women with polycystic ovarian
syndrome (PCOS)
• A1C ≥5.7%, IGT, or IFG on previous
testing
• Other clinical conditions associated
with insulin resistance (e.g., severe
obesity, acanthosis nigricans)
• History of CVD
*At-risk BMI may be lower in some ethnic groups.
1. Testing should be considered in all adults who are overweight
(BMI ≥25 kg/m2*) and who have one or more additional risk factors:
ADA. Testing in Asymptomatic Patients. Diabetes Care 2012;35(suppl 1):S14. Table 4.

51. Pathogenesis:
Abnormalities of glomerular endothelial barrier:
Stage of Increased filtration
Reduction of renal tubular cell albumin degradation
Glomerular hypertension
Inflammation
Oxidative stress
All this cause albuminuria