DIABETIC NEPHROPATHY

Dr. P. Rahul
Nephrologist
INTRODUCTION
Microvascular complication
Occurs in upto 40% of diabetes patients
Emerging as a leading cause of ESRD in India
Mortality of ESRD patients with Diabetes Mellitus is higher
than in ESRD patients without Diabetes
However all diabetic patients with ESRD do not have DN as
underlying cause of ESRD.

EPIDEMIOLOGY - DIABETES
Number of diabetics world wide: 171 million.
By 2030 - 334 million.
USA - 8%
Europe - 7%
India - 12-15% (Urban)
Type I ~ 10%
Type II > 90%

EPIDEMIOLOGY
General incidence of Diabetic Nephropathy:
30-40 % of patients with Type I DM
25-40 % of patients with Type II DM
20 - 30 % of Type I DM Progress to ESRD
10 20 % of Type II DM Progress to ESRD

> 30 % of all chronic renal failure patients have Diabetic
Nephropathy

Diabetic Kidney 2007
EPIDEMIOLOGY
In Type 1 DM with Microalbuminuria:
30 80 % develop albuminuria in 10-15 yrs
50-78% develop ESRD in 10-18 yrs
In Type 2 DM :
8-10% have microalbuminuria at diagnosis
20-40% develop albuminuria in 10-15 yrs
20% progress to ESRD in 10-18 yrs



Diabetic Kidney 2007

Genetic Susceptibility

Likelihood of developing DN is markedly increased in patients
with a diabetic sibling or parent who has diabetic nephropathy.
RISK FACTORS FOR DN

Age
Increasing age, along with increasing duration of diabetes,
was associated with increased risk for developing
albuminuria.
RISK FACTORS FOR DN

Blood Pressure
Association between the subsequent development of
nephropathy and higher systemic pressures.
RISK FACTORS FOR DN

Glycemic Control
Diabetic nephropathy is more likely to develop in patients with
worse glycemic control (higher HbA1c levels).
RISK FACTORS FOR DN

Race
Increased incidence in African-Americans, Pima Indians,
Asians
RISK FACTORS FOR DN

Obesity
Associated with an increased risk of chronic kidney disease
among patients with diabetes.
RISK FACTORS FOR DN

Smoking
Associated with increases in albuminuria and the risk of end-
stage renal disease and of decreased survival once dialysis is
begun.
RISK FACTORS FOR DN

NATURAL HISTORY
DN develops after a well defined time period and is usually
associated with retinopathy
DN is characterised by certain well defined stages and presents with
proteinuria , hypertension and renal failure.
All renal disease in a diabetic is not Diabetic Nephropathy
TIME TO ONSET
20 to 30 percent will have microalbuminuria in 15 years
Less than half of these patients will progress to overt
nephropathy.
Onset of overt nephropathy is typically between 10 and 15
years after the onset of the disease.
Those patients who have no proteinuria after 20 to 25 years
have a risk of developing overt renal disease of only about 1
percent per year.


RELATION BETWEEN DIABETIC
NEPHROPATHY AND RETINOPATHY
Patients with nephropathy and type 1 diabetes almost always
have other signs of diabetic microvascular disease, such as
retinopathy and neuropathy
Relationship between diabetic nephropathy and retinopathy is
less predictable in type 2 diabetes
Type 2 diabetics with marked proteinuria and retinopathy most
likely have diabetic nephropathy, while those without
retinopathy have a high frequency of non-diabetic glomerular
disease
30 percent of type 2 diabetics with renal insufficiency have non-
diabetic renal disease
RELATION BETWEEN DIABETIC
NEPHROPATHY AND RETINOPATHY
2007 K/DOQI Guidelines for diabetes and chronic kidney
disease suggest that chronic kidney disease should be
attributed to diabetes in most patients with diabetes if
microalbuminuria and diabetic retinopathy are both present.
By comparison, other causes of CKD should be entertained if
diabetic retinopathy is absent
RELATION BETWEEN DIABETIC
NEPHROPATHY AND RETINOPATHY
Non Diabetic renal disease
suspected when.
No retinopathy
Absence of albuminuria
Rapid increase in serum creatinine.
Presence of active urinary sediment.

Stage Duration Features
I Hypertrophy < 2 yrs Nephromegaly, No laboratory
abnormalities, RPF
II Histological
abnormalities
> 2 yrs Initial morphological lesions :
GBM thickness,
Mesangium
III Incipient
nephropathy
10-20
yrs
Microalbuminuia, GFR - N
Hypertension (50%)
IV Overt
nephropathy
15-20
yrs
Persistent proteinuria, HTN
(70%), RPF & GFR
V End stage
renal disease
20-40
yrs
GFR < 10%
Hypertension (90%)
MOGENSENS STAGING
Staging well defined in Type 1 DM
In Type 2
15-30% patients can have Microalbuminuria at diagnosis
(Stage 3)
2-8 % can have Overt proteinuria at diagnosis (Stage 4)

SCREENING
When ?
Type 1 DM
Young patients from puberty
Adults - 5 yrs after diagnosis
Type 2 DM
At diagnosis
Yearly thereafter in both


How ?
Spot Urine albumin-creatinine ratio
24 hour urine gold standard
Dipstick/Micral

ALBUMINTO-CREATININE RATIO
Calculation of albumin-to- creatinine ratio in an untimed urine
specimen.
A value above 30mg/g or 0.03mg/mg suggests that albumin
excretion is above 30mg/d and hence microalbuminuria is
probably present.
Almost 100% sensitivity for detection of microalbuminuria.
Preferred screening strategy for all diabetic patients.
MICROALBUMINURIA
Persistent albumin excretion between 30 and 300 mg/day (20
to 200 g/min) is called microalbuminuria
At least 2/3 samples positive for microalbuminuria in 6
months.
No e/o infection, hyperglycemia, no prior exertion.

Significance:
Type I DM:
Predicts overt nephropathy
Type II DM:
Predicts CV mortality
Predicts nephropathy

MICROALBUMINURIA
MICROALBUMINURIA AND GFR
Loss of renal function - defined as an estimated decrease in
GFR of more than 3.3 percent per year occurred in
9% of patients with normoalbuminuria
16% - regression of microalbuminuria.
32% - Stable microalbuminuria
68% - Progressive microalbuminuria
PROGRESSION TO
MACROALBUMINURIA

Albumin excretion above 300 mg/day (200 g/min) is
considered to represent macroalbuminuria
Rate of progression from microalbuminuria to
macroalbuminuria was 2.8 percent per year
Mean rate of loss of GFR in patients with macroalbuminuria
was 0.93 mL/min per month
MANAGEMENT OF DN
Primary
prevention
Secondary
prevention
Tertiary
prevention
ESRD
MA DM
Overt
nephropathy
Ref. Tobe SW et al. CMAJ 2002; 167(5): 499-503
LIFE STYLE MODIFICATION

Ideal body weight

Abstinence from alcohol

Cessation of smoking

Regular exercise


PRIMARY PREVENTION

Glycemic control
Strict glycemic control is recommended in all patients
because of its beneficial effects on microvascular
complications
LANDMARK TRIALS

Type I DM - DCCT

Type II DM - UKPDS

Tight glycemic control leads to significant decrease in retinopathy,
neuropathy and nephropathy and macrovascular complications
Adapted from Diabetes Care ,Jan 2007
Key concepts in setting glycemic goals:

A1C is the primary target for glycemic control
Ideal HbA1C < 7%
More stringent glycemic goals (i.e., a normal A1C, <6%)
may further reduce complications at the cost of increased
risk of hypoglycemia and cardiovascular events.


Glycemic Control
Diet
Exercise
Insulin
Oral hypoglycemic agents

OHAs in CKD

OHA s in CKD
ACE INHIBITORS OR ARBS
Three randomized, placebo-controlled trials of 256 to 3326
patients with diabetes and normoalbuminuria (RASS,
EUCLID, DIRECT) showed no benefit from angiotensin
inhibition
There is no evidence that ACE inhibitors or ARBs are
effective for the primary prevention of microalbuminuria in
patients with diabetes who are normoalbuminuric and
normotensive.
SECONDARY PREVENTION

How to control proteinuria?
Dietary Management
0.6-0.8 g/kg protein day, normal (1-1.2 gm/kg) if on dialysis
High Biological value proteins
Vegetable protein better
Essential amino acids
Ketoanalogues of essential amino acids
Salt intake and proteinuria
high salt intake has been shown to blunt the antiproteinuric
effects of angiotensin inhibitors in patients with non-diabetic
kidney disease.
Salt restriction and/or diuretics enhance the effect of renin-
angiotensin blockade on proteinuria
Salt restriction to 70 meq/day has been found to enhance
the antiproteinuric effects of ARB in patients with type 2
diabetes
ACEI & ARBS
Beyond BP Control

Proteinuria
RAS
Growth factors
Free oxygen radicals
Antifibrotic role
Sodium absorption




ACE inhibitor plus ARB
The superiority of combination therapy with an ACE inhibitor
and an ARB compared to either therapy alone in decreasing
proteinuria has been established in both type 1 and type 2
diabetes
combination therapy with an ACE inhibitor and ARB is
associated with a higher incidence of adverse effects
ARB plus aliskiren
The first effective oral direct renin inhibitor
Aliskiren lowers blood pressure to a degree comparable to
most other agents
In the AVOID trial, aliskiren plus losartan was associated with
a significant 20 percent greater reduction in proteinuria
compared to losartan alone
Aldosterone antagonism
Aldosterone antagonists appear to reduce proteinuria when
used alone, and to have an additive effect on proteinuria
when used in combination with an ACE inhibitor or an ARB in
both type 1 and type 2 diabetes
Spironolactone, Eplerenone

Other antihypertensive drugs
Diltiazem and verapamil appear to be as consistently effective
as an ACE inhibitor or ARB in lowering protein excretion in
diabetic patients


Other agents
Pentoxifylline lowers proteinuria
Weight reduction
Marked decreases in proteinuria may be observed in obese
diabetics who lose weight.
HYPERTENSION AND
PROGRESSION
Transmission to glomerulus initiation of sclerosis
DBP > 90 mm hg progression twice as fast
MAP of 90 almost normalizes rate of decline (2
ml/min/year)
In proteinuric hypertensives effects more marked
HYPERTENSION

1. Diet
2. Exercise
3. Drugsicsers
calcium antagonists
* Lowering BP by any drug beneficial

ACEI
ARBs
Ca channel blockers
Blockers
Diuretics
HYPERLIPIDEMIA AND
PROGRESSION
Dyslipidemia implicated in the pathogenesis of progression
lipids nephrotoxic.
Increase glomerular capillary pressure.
Mesangial changes structural and functional (lipid peroxidation
of LDL foam cells )
Lipoprotein thrombi in the glomerular capillaries

HYPERLIPIDEMIA TREATMENT
Diet
Exercise
Drugs
Statins
Fibrates
ANEMIA AND PROGRESSION

Enhances renal hypoxia
Stimulates release of profibrotic cytokines

Target Hb 12 g/dL


Erythropoietin therapy and correction of anemia may slow CKD progression

RENAL REPLACEMENT THERAPY
Dialysis
Hemodialysis
Peritoneal Dialysis
Transplant
NEWER THERAPIES
Inhibition of TGF-beta (Monoclonal Antibodies to TGF-beta)
appears to ameliorate diabetic nephropathy in experimental
models of diabetes and in preliminary human studies.
Protein Kinase C Inhibitors: Ruboxistaurine
Antifibrotic agents: Tranilast
Endothelin antagonist: Bosentan


NEWER THERAPIES
PPAR-gamma agonists
thiazolidinediones (eg, pioglitazone and rosiglitazone) -
variety of beneficial effects in animal models of diabetic
nephropathy, such as reductions in fibrosis, mesangial cell
proliferation, and inflammation
reduce urinary albumin excretion at various stages of
nephropathy and reduce blood pressure


NEWER THERAPIES
Reduction of Advanced Glycation end products:
ACE I & ARB
Metformin
Aminoguanidine (Pinagedine)
Pyridoxamine
Lipoic acid
Vitamin E
Benfotiamine
Monoclonal Ab to Amadori glycated albumin


SUMMARY
Diabetic renal disease reaching epidemic proportions
All renal disease in a diabetic not diabetic nephropathy
Early detection important Spot urine test/MICRAL
Multi-pronged approach
Diet, Glycemic control, Blood pressure control, ACEI/ARBs
Renal replacement therapies are available but a poor substitute
for prevention

THANK YOU