For gp

1. DIABETIC NEPHROPATHY:CLINICAL
MANIFESTATION,NATURAL HISTORY,
PREVENTION AND TREATMENT
DR AHMAD TANWEER
UNIT-DR(PROF)ASHOK SHANKER SINGH

2. Diabetic nephropathy is characterized by
• Persistent albuminuria (>300 mg/24 hr)
• Presence of diabetic retinopathy
• Absence of clinical or laboratory evidence of
other kidney or renal tract disease.
• Declining GFR

3. Pathology of Diabetic Nephropathy in Patients with
Type 1 Diabetes and Proteinuria
ALWAYS PRESENT
1.Glomerular basement membrane thickening.
2.Tubular basement membrane thickening.
3.Mesangial expansion with predominance of
increased mesangial matrix.
4.Interstitial expansion with predominance of
increased extracellular matrix material.

4. OFTEN OR USUALLY PRESENT
1. Kimmelstiel-Wilson nodules (nodular
glomerulosclerosis)
2. Global glomerulosclerosis
3. Focal segmental glomerulosclerosis
4. Atubular glomeruli
5. Foci of tubular atrophy
6. Afferent and efferent arteriolar hyalinosis

5. SOMETIMES PRESENT
1. Hyaline caps or fibrin caps (Highly
characteristic of diabetic nephropathy)
2. Capsular drops (Highly characteristic of
diabetic nephropathy)
3. Atherosclerosis.
4. Glomerular micro-aneurysms.

6. Mechanism of hyperglycemia induced
damage
Four major hypothesis have been generated:
• Increased polyol pathway flux
• Increased hexosamine pathway flux
• Increased intracellular formation of advanced
glycation end products
• Activation of protein kinase C

7. Comparison of nephropathy in type1
diabetes and type2 diabetes
• About one third of the patients with type2 had
changes similar to those typically seen in type1
diabetes
• One third had marked increase in percentage of
sclerosed glomeruli associated with severe
tubulointerstitial lesions, whereas non-sclerosed
glomeruli showed only mild diabetic changes
• In third group there were typical changes of
diabetic nephropathy and superimposed changes
of proliferative glomerulonephritis, membranous
glomerulopathy and so on

8. • Renal structure changes in type2 diabetes are
more heterogeneous and diabetic
nephropathy lesions are less severe than in
type1 patient with similar albuminuria level
• Non diabetic glomerulopathy is seldom seen
in proteinuric type 1 diabetic patients,
whereas this condition is common in
proteinuric type 2 diabetic patients without
retinopathy

9. NATURAL HISTORY

10. NATURAL HISTORY OF DIABETIC NEPHROPATHY
FIVE STAGES
Stage 1: Hyperfiltration
• Increased Glomerular Filtration Rate (GFR >90ml/min)
• Concomitant renal hypertrophy (glomerular and
tubular)
• Various factors contributing are:
1. Intra renal hemodynamic abnormalities
2. TGF-β
3. Increased salt absorption
4. Osmotic load and toxic effect of high sugar levels on
kidney cells

11. Stage 2 : The Silent Stage
• The GFR has returned to normal with no
evidence of albuminuria
 Glomerular damage occurs in the form of
basement membrane thickening and
mesangial expansion.
Ambulatory BP monitoring studies have shown
modest rise in BP and absence of nocturnal dip

12. Stage 3: Incipient nephropathy
/Microalbuminuria
• Urine AER has increased to 30 to 300 mg/24 hrs
• Renal functions could be normal or reduced
• 30-50% of patients may show reversal of
microalbuminuria
• Persistent microalbuminuria , if untreated, will
progress to end-stage renal disease (ESRD).
• Therefore, all diabetes patients should be
screened for microalbuminuria on a routine
basis.

13. Stage 4 : Macroalbuminuria/Overt
Nephropathy
• The urine AER is more than 300 mg of albumin
in a 24-hour period.
• Over two thirds of patient in this stage have
Hypertension .
• If untreated a vicious cycle of progressive
renal impairment develops leading to ESRD.

14. Stage 5: Uremia
GFR has fallen to <15 ml/min and renal
replacement therapy (i.e., haemodialysis,
peritoneal dialysis, kidney transplantation) is
needed.

15. Diabetic nephropathy is a clinical syndrome
characterized by
1)Persistent albuminuria
2)Decline in GFR
3)Raised arterial BP
4)Enhanced cardiovascular morbidity and
mortality
Albuminuria is the first sign and peripheral edema
is the first symptom of diabetic nephropathy

16. Risk factors associated with progression

17. Proteinuria induced renal damage

18. Screening and diagnosis of diabetic nephropathy
• Diabetes should be screened annually with serum
creatinine and eGFR and urine alb:creatinine
(ACR)
◦ Starting 5 yrs after diagnosis of type 1
◦ Starting at the diagnosis of type II
• Elevated urine ACR confirmed ≥ 2 times and not
in setting of UTI ,acute febrile illness, vigorous
exercise, uncontrolled hypertension, and heart
failure
◦ Microalbuminuria: ACR 3-30 mg/mmol
◦ Macroalbuminuria: ACR >300 mg/mmol

20. FACTORS AFFECTING URINARY ALBUMIN EXCRETION
INCREASED AER DECREASED AER
Strenuous exercise
 Poorly controlled DM
 Heart failure
 UTI
 Acute febrile illness
 Uncontrolled HPT
 Hematuria
 Menstruation
 Pregnancy
NSAIDs
 ACE inhibitors

22. • Screening should be done when the person is
free from acute illness and with stable glucose
levels
• Early morning urine sample is preferred
• Serum creatinine level should also be
measured annually
• Recently serum Cystatin C - A naturally
circulating protein, freely filtered by
glomerulus has been suggested as an
alternative to creatinine measurement.

23. Treatment
Major therapeutic interventions include -
• Control of blood glucose to near normal level
• Antihypertensive treatment
• Lipid lowering therapy
• Restriction of dietary proteins
• Cessation of smoking

24. Glycemic control
Primary prevention:
• Diabetic Control and Complications Trial
showed that intensive glycemic control
reduces the occurrence of microalbuminuria
• ADVANCE study and VETERAN trial recently
confirmed similar findings.

25. Secondary prevention :
• UKPDS proves that tight glycemic control reduces
progression from microalbuminuria to overt
nephropathy
• A recent trial also confirms that ESRD
development was retarded by multifactorial
interventions
Nephropathy:
• Once overt nephropathy develops , results are
disappointing regarding metabolic control in
preventing further progression of disease

26. KDIGO guidelines for management of
hyperglycemia and general diabetes care in CKD
• Target Hemoglobin A1c(HbA1c) of 7.0% to
prevent or delay progression of the
microvascular complications of diabetes,
including DKD.
• No treatment if HbA1c target is <7.0% in
patients at risk of hypoglycemia.

27. • Target HbA1c can be extended to > 7.0% in
individuals with co-morbidities or limited life
expectancy
• Metformin to be continued in people with
GFR ≥ 45 ml/min/1.73 m(GFR categories G1-G3a)
Its use should be reviewed in those with GFR 30–
44 ml/min/1.73 m(GFR category G3b)
Discontinued in people with GFR <30
ml/min/1.73 m(GFR categories G4-G5) and risk of
hypoglycemia.

30. Blood pressure control
• ACE-I or ARB’s are not recommended for the primary
prevention of diabetic nephropathy in normotensive
normoalbuminuric patients with diabetes
• ACE inhibitors and ARB’s are effective in slowing the
progression of kidney disease characterized by
microalbuminuria in hypertensive patients with type 1
or type 2 diabetes.
• ACE inhibitors, ARBs, and nondihydropyridine calcium
channel blockers have a greater anti-proteinuric effect
than other antihypertensive classes in hypertensive
patients with diabetic nephropathy.

31. • Dihydropyridine calcium channel blockers, when
used alone in the absence of ACE inhibitors or ARB’s
are less effective than other agents in slowing
progression of diabetic nephropathy.
• ADA states “ In patients with type 2 diabetes,
hypertension, macroalbuminuria and renal
insufficiency ARBs have shown to delay progression”

32. KDIGO GUIDELINES FOR MANAGEMENT OF
HYPERTENSION IN DIABETIC NEPHROPATHY AND
PROTIENURIA
• Both diabetic and non-diabetic adults with CKD
and urine albumin excretion <30 mg/24 hours
whose office BP is consistently >140/90 mm Hg,
be treated with BP-lowering drugs to maintain a
BP that is consistently ≤ 140/90 mm Hg.
• Both diabetic and non-diabetic adults with CKD
and with urine albumin excretion of >30 mg/24
hours whose office BP is consistently >130/80 mm
Hg, be treated with BP-lowering drugs to maintain
a BP that is consistently ≤ 130/80 mm Hg.

33. • ARB or ACE-I can be used in diabetic adults
with CKD and urine albumin excretion of 30–
300 mg/24 hours.
• ARB or ACE-I can be used in both diabetic and
non-diabetic adults with CKD and with urine
albumin excretion of >300 mg/24 hours
• There is insufficient evidence to recommend
the combination of an ACE-I with an ARB to
prevent progression of CKD.

34. Precautions taken while starting an ACE-I or an ARB
• Monitoring of blood pressure, potassium, and
serum creatinine level is important.
• Potassium level up to 5.5 mEq/L and an increase
in serum creatinine up to 30% from baseline
within the first three months with close
monitoring is tolerable
• Medication needs to be reduced or discontinued
if potassium levels remain elevated at > 5.5mEq/L
or if the serum creatinine continues to rise or
does not improve.

35. • Avoid in people with suspected functional renal
artery stenosis
• Start at lower dose in people with GFR <45
ml/min/1.73 m
• Assess GFR and measure serum potassium within
1 week of starting or following any dose
escalation
• Temporarily suspend during intercurrent illness,
planned IV radiocontrast administration, bowel
preparation prior to colonoscopy, or prior to
major surgery
• Do not routinely discontinue in people with GFR
<30 ml/min/1.73 m as they remain
nephroprotective

37. TREATMENT GOAL FOR LIPIDS IN DIABETIC
NEPHROPATHY
• Low-density lipoprotein <2.6 mmol/L (100
mg/dL)
• High-density lipoprotein >1 mmol/L (40
mg/dL) in men, >1.3 mmol/L (50 mg/dL) in
women
• Triglycerides <1.7 mmol/L (150 mg/dL)

38. KDIGO guidelines for management of
dyslipidemia in diabetes and CKD
• Dyslipidemia is common in people with
diabetes and CKD. Cardiovascular events are a
frequent cause of morbidity and mortality in
this population.
• Lowering low-density lipoprotein cholesterol
(LDL-C) with statin-based therapies reduces
risk of major atherosclerotic events in patients
with CKD including those with diabetes.

39. • LDL-C lowering medicines, such as statins or
statin+ezetimibe combination reduces risk of
major atherosclerotic events in patients with
diabetes and CKD, including those who have
undergone kidney transplant.
• Not recommended to initiate statin therapy in
patients with diabetes who are treated by
dialysis.

40. Dietary Protein Restriction
• A low protein diet reduces urinary albumin
excretion and hyperfiltration independent of
changes in glucose control and blood pressure.
KDIGO GUIDELINE FOR PROTIEN INTAKE
• Lowering protein intake to 0.8 g/kg/day in adults
± diabetes and GFR<30 ml/min/ 1.73 m2(GFR
categories G4-G5) with appropriate education.
• Avoiding high protein intake (>1.3 g/kg/day) in
adults with CKD at risk of progression

41. MANAGEMENT OF ANEMIA IN DIABETIC
NEPHROPATHY
• In diabetic patient with renal failure anemia is more
frequent and more severe at any given level of GFR.
• In patients with DN, anemia is an independent risk
factor associated with decline in GFR.
• Renal hypoxia resulting from anemia aggravates
interstitial fibrosis by stimulation of factors like TGF-β
and VEGF.
• Hypoxia-inducing factor-1 (HIF-1) and ANG-II also
play a major role.

42. KDIGO GUIDELINES FOR ANEMIA
• Anemia in adults and children >15 years with CKD is
when the Hb concentration is <13.0 g/dl in males
and <12.0 g/dl in females
To identify anemia in patients with CKD by measuring Hb level
• When clinically indicated in patients with GFR >60
ml/min/1.73 m2(GFR categories G1-G2)
• Annually in patients with GFR 30–59 ml/min/1.73 m2
(GFR categories G3a-G3b)
• Twice a year in patients with GFR<30 ml/min/1.73 m2
(GFR categories G4-G5)
Treatment of anemia with recombinant human EPO and
darbepoetin-α

43. Treatment of End-Stage Renal Disease (ESRD)
1. Transplantation(kidney only, simultaneous
pancreas with kidney, pancreas after kidney)
2. Hemodialysis
3. Continuous ambulatory peritoneal dialysis

44. HEMODIALYSIS
• Renal replacement therapy should be started
earlier than in non diabetic patient at an
• Intradialytic hypotension is common in diabetic
patient on dialysis because of autonomic
neuropathy and disturbed left ventricular
compliance
• Following approach is used to avoid intradialytic
hypotension - Long dialytic session, omission of
antihypertensive drugs before dialytic session,
controlled ultrafiltration, correction of anemia by
EPO therapy, alternative modalities such as CAPD

45. • High prevalence of cardiovascular
complications in diabetic patients entering
dialysis programme
• Diabetic patients are also more prone for
cardiac arrest during dialysis session
• Dialysis partially reverses the insulin resistance
and requirement compared prior to dialysis

46. PERITONEAL DIALYSIS
• According to heaf and co worker, during the first
2 years, survival is better for diabetic patient
treated with CAPD compared to HD
• Survival advantage no longer demonstrated
beyond 2 years as by then residual renal function
has already decayed
• CAPD provides slow and sustained ultra filtration
without rapid fluctuation of fluid volume and
electrolyte concentration, a feature that is
advantageous for BP control and prevention of
heart failure

47. KIDNEY TRANSPLANT
• Survival of diabetic patients with kidney graft
is worse compared to non diabetic patients.
And survival of diabetic nephropathy patients
on dialysis is poorer when compared to
patients with kidney graft.
• Simultaneous kidney with pancreas
transplantation(SPK) should be the preferred
treatment for type1 DM who meet the
selection criteria: Age <55 years and GFR<40.
Exclusion criteria for SPK: Active smoking,
morbid obesity and uncorrected CVD

48. • Pancreas after kidney transplantation – An
alternative strategy, must be considered in a
diabetic patient who has a living kidney donor.
Firstly the living kidney is transplanted and
subsequently once stable renal function is
achieved (GFR>50 ml/min), cadaveric
pancreas is transplanted
• Results of Islet cell transplantation are inferior
to whole pancreas transplantation

49. Agents with negative result or potential harm
• Endothelin antagonists –
In diabetic nephropathy, endothelin 1 levels
are increased and contribute to proteinuria
and glomerulosclerosis.
The ASCEND trial studied the effects of
endothelin A receptor antagonist in type 2 DM
population and found- Increase in cardiac
deaths, higher fluid retention and congestive
heart failure despite a reduction in the
albumin:creatinine ratio

50. • Bardoxolone methyl –
Bardoxolone is an antioxidant with anti-
inflammatory activity
Early studies seemed promising in improving
GFR but the BEACON trial was terminated
early due to increased adverse events and
mortality noted in the Bardoxolone arm

51. • AGE inhibitor-
Aminoguanidine (Pimagedine), an AGE
inhibitor was tested in a randomized control
trial for type 2 DM but was terminated due to
other significant adverse events, such as
glomerulonephritis and lupus like reactions.
 Pyridoxine, another AGE inhibitor was studied
in a randomized control trial, but there was no
significant improvement in renal function or
albuminuria

52. Some potential therapy for diabetic
nephropathy
• Sodium coupled glucose co-transporter 2 (SGLT2)
inhibitors-
 90% of glucose is absorbed through SGLT2 found
in kidney and intestine.
 A phlorizine derivative, able to inhibit the activity
of this transporter and result in glycosuria.
However this may increase the risk of
genitourinary tract infection and volume
depletion by osmotic diuresis

53. • Connective tissue growth factor(CTGF)-
Increases the activity of pro-fibrotic cytokines
such as TGF-β and promotes fibrosis.
FG309 a human monoclonal antibody to CTGF
has shown to reduce proteinuria in type 2 DM

54. • VITAMIN-D:
Vitamin-D has shown to have an inhibitory
effect on the RAAS and suppresses the plasma
renin expression and activity.
Vit-D also exerts anti inflammatory effect by
decreasing pro-inflammatory cytokines.

55. • INHALED INSULIN approved by FDA in 2014 –
AFREZZA
1. Rapid acting insulin taken before each meal or
soon after starting the meal
2. Doesn’t replace the need of injectable long-
acting insulin, hence not suitable for diabetic
emergencies such as DKA
3. Common side effects - Low blood sugar, cough,
scratchy/sore throat
4. Should not be used in smokers and individuals
with lung disease.