2. Definition
Persistent albuminuria (>300 mg/24 hr or 200 μg/min) is
the hallmark of diabetic nephropathy.
Can be diagnosed clinically if the following additional
criteria are fulfilled:
Presence of diabetic retinopathy
Absence of clinical or laboratory evidence of other kidney
or renal tract disease.
3. Clinically, diabetic nephropathy is characterized by a
progressive increase in proteinuria and decline in GFR,
hypertension, and a high risk of cardiovascular morbidity
and mortality.
4. Approximately 40% of patients with types 1 or 2 diabetes
develop nephropathy, but due to the higher prevalence of
type 2 diabetes (90%) compared to type 1 (10%), the
majority of patient with diabetic nephropathy have type 2
disease.
5. Microalbuminuria appears 5–10 years after the onset of
diabetes.
It is currently recommended to test patients with type 1
disease for microalbuminuria 5 years after diagnosis of
diabetes and yearly thereafter and, to test type 2
patients at the time of diagnosis of diabetes and yearly
thereafter
7. Pathology
Thickening of the glomerular
basement membrane (GBM) is the
first change that can be quantitated
Thickening of tubular basement
membranes parallels this GBM
thickening .
8. Within 1–2 years after the onset of clinical diabetes,
morphologic changes appear in the kidney.
Thickening of the GBM is a sensitive indicator for the
presence of diabetes but correlates poorly with the
presence or absence of clinically significant nephropathy
9. The composition of the GBM is altered notably with a loss
of heparin sulfate moieties that form the negatively
charged filtration barrier.
This change results in increased filtration of serum
proteins into the urine, predominately negatively charged
albumin
10. The expansion of the mesangium due to the
accumulation of extracellular matrix correlates with the
clinical manifestations of diabetic nephropathy
The diffuse and generalized process of mesangial
expansion has been termed diffuse diabetic
glomerulosclerosis .
Nodular glomerulosclerosis (Kimmelstiel- Wilson nodular
lesions) represents areas of marked mesangial
expansion appearing as large round fibrillar mesangial
zones, often with extreme compression of the adjacent
glomerular capillaries .
11. Afferent and efferent glomerular arteriolar hyalinosis can
also be detected within 3 to 5 years after onset of
diabetes.
12. Renal extracellular membranes, including GBM,
TBM and Bowman’s capsule, demonstrate
increased intensity of immunofluorescent linear
staining for plasma proteins, especially albumin and
immunoglobulin G .
Because these changes are seen in all diabetic
patients and appear unrelated to disease risk, their
only clinical importance is that they should not be
confused with other entities, such as anti- GBM
antibody disorders.
13. Clinical diabetic nephropathy is primarily the
consequence of ECM accumulation, which must result
from an imbalance in renal ECM dynamics whereby over
many years the rate of ECM production exceeds the rate
of removal.
14. Direct effects of hyperglycemia on the actin cytoskeleton of renal
mesangial and vascular smooth-muscle cells as well as diabetes-
associated changes in circulating factors such as atrial natriuretic
factor, angiotensin II, and insulin-like growth factor (IGF) may
account for this.
Sustained glomerular hypertension increases matrix production,
alterations in the GBM with disruption in the filtration barrier (and
hence proteinuria), and glomerulosclerosis.
factors have also been identified that alter matrix production,
including the accumulation of advanced glycosylation end
products, circulating factors including growth hormone, IGF-I,
angiotensin II, connective tissue growth factor, TGF-β, and
dyslipidemia.
16. The deterioration of renal function in patients with
diabetes typically occurs over the course of several
phases, which include
1) hyperfiltration,
2) microalbuminuria,
3) overt nephropathy +/- the nephrotic syndrome,
4) ESRD
17. Normoalbuminuria with hyperfiltration
Albuminuria less than 30mg/day
Hypertension and albuminuria are typically not present
during this phase.
Characteristic feature is a GFR above the upper normal
range for age-matched healthy nondiabetic subjects.
Intensified insulin treatment and control to near-normal
blood glucose levels reduce GFR toward normal levels
after a period of days to weeks in both type 1 and type 2
diabetic patients.
18. A recent meta-analysis, based on 10 cohort studies
following 780 patients, found a hazard ratio of 2.71 for
progression to microalbuminuria in patients with
hyperfiltration.
19. Microalbuminuria
Urinary albumin excretion within the microalbuminuric
range (30 mg to 300 mg/24 hr) in at least two out of three
consecutive nonketotic sterile urine samples is definied
as persistent microalbuminuria.
Urinary albumin/creatinine ratio is measured, and
microalbuminuria is defined as 30 to 300 mg/g creatinine.
20. A normal urinary β2-microglobulin excretion rate in
microalbuminuria suggests that albumin derives from
enhanced glomerular leakage rather than from reduced
tubular reabsorption of protein.
21. Factors causing microalbuminuria are
1. Loss of glomerular charge selectivity
2. Changes in podocyte number and morphology.
3. Elevated filtration both at rest and during exercise
compared with normal controls
4. Glomerular hypertension with or without systemic
hypertension.
22. Microalbuminuria as a Predictor of
Nephropathy
Type 1 diabetic patients with microalbuminuria have a
median risk ratio of 21 for developing diabetic
nephropathy, whereas the risk ratio for developing
diabetic nephropathy ranges from 4.4 to 21 (median =
8.5) in type 2 diabetic patients with microalbuminuria.
23. It has been suggested that 58% of microalbuminuric
patients revert to normoalbuminuria with good glycemic
control.
In type 1 diabetics, the onset of microalbuminuria
typically coincides with the development of hypertension.
The presence of hypertension during this phase is more
variable among type 2 diabetics.
24. Microalbuminuria is a strong predictor of total and
cardiovascular mortality and cardiovascular morbidity in
diabetic patients.
Similarly, microalbuminuria predicts coronary and
peripheral vascular disease, death from cardiovascular
disease and stroke in the general nondiabetic population.
25. Diabetic nephropathy
Diabetic nephropathy is a clinical syndrome
characterized by
1. Persistent albuminuria (>300 mg/24 hr, or 300 mg/g
creatinine).
2. A decline in GFR.
3. Raised arterial blood pressure.
4. Enhanced cardiovascular morbidity and mortality.
26. albuminuria is the first sign, peripheral edema is often the
first symptom of diabetic nephropathy.
Fluid retention is frequently observed early in the course
of this kidney disease; that is, at a stage characterized by
well preserved renal function and only a modest
reduction in serum albumin level.
27. Rate of decline in GFR is highly variable across
individuals, ranging from 2 to 20 mL/min/yr, with a mean
approximating 12 mL/min/yr and is similar in both types
of diabetes.
29. Systemic hypertension
Systemic hypertension is transmitted to the single
glomerulus, which results in increases in glomerular
hydrostatic pressure in such a way as to lead to
hyperperfusion and increased capillary pressure –
Glomerular hypertension.
Impaired or abolished renal autoregulation of GFR and
renal plasma flow as demonstrated in type 1 and type 2
diabetic patients with nephropathy increases vulnerability
to hypertension or ischemic injury of glomerular
capillaries
30. RAAS
Several components of the RAAS are elevated and are
considered to contribute to the progression of diabetic
nephropathy.
There is increased angiotensin converting enzyme (ACE)
activity and reduced expression of ACE2 in patients with
diabetic nephropathy compared with controls and
patients with nondiabetic kidney disease.
31. Increased aldosterone levels which cause upregulation of
the prosclerotic growth factors plasminogen activator
inhibitor-1 and transforming growth factor-β1, as well as
promotion of macrophage infiltration, which consequently
leads to renal fibrosis.
32. Several gene variants have been investigated as risk
factors for diabetic nephropathy.
the insertion/deletion (I/D) polymorphism of the ACE
gene (ACE/ID), which is strongly associated with the
level of circulating ACE and increased risk of coronary
heart disease in nondiabetic and diabetic patients
33. Extrarenal Complications in Diabetic
Nephropathy
Diabetic retinopathy
More than 90% of patients with type 1 diabetes and
nephropathy have diabetic retinopathy
so the absence of retinopathy in type 1 patients with
proteinuria should prompt consideration of a diagnosis
other than diabetic nephropathy
only 60% of patients with type 2 diabetes with
nephropathy have diabetic retinopathy.
34. Macroangiopathies (e.g., stroke, carotid artery stenosis,
coronary heart disease, and peripheral vascular disease)
are two to five times more common in patients with
diabetic nephropathy.
35. SCREENING AND DIAGNOSIS
Screening for diabetic nephropathy must be initiated at
the time of diagnosis in patients with type 2 diabetes (14),
since 7% of them already have microalbuminuria at that
time
For patients with type 1 diabetes, the first screening has
been recommended at 5 years after diagnosis
36. Puberty, poor glycemic control and poor lipid control are
independent risk factors for micro albuminuria .Therefore,
in type 1 diabetes, screening for micro albuminuria might
be performed 1 year after diabetes diagnosis in these
patients.
If micro albuminuria is absent, the screening must be
repeated annually for both type 1 and 2 diabetic patients.
37. diagnosis
Renal biopsy is the gold standard
A renal biopsy may be deferred with the assumed
diagnosis of diabetic nephropathy in the context of
1. Macro albuminuria (>300 mg/24 hours) that has
developed progressively,
2. Microalbuminuria (30-300 mg/24 h) with retinopathy,
3. Microalbuminuria in patients with diabetes for more
than 10 years .
38. Not DN if…
the presence of
1. haematuria,
2. nephrotic range proteinuria at the time of diagnosis of
diabetes, or
3. the presence other systemic disease processes
including autoimmune disease, hepatitis C, or human
immunodeficiency virus
warrant the consideration of another potentially treatable
condition that would require a renal biopsy to diagnose.
40. RAAS inhibition
Monotherapy with either an ACE inhibitor or ARB is
currently recommended as first line therapy for diabetic
patients with microalbuminuria or diabetic nephropathy.
Beyond the impact of blood pressure lowering, inhibition
of the RAAS additionally slows the progression of
diabetic nephropathy compared to other antihypertensive
drugs
41. General recomendations
1. The current recommendations outlined by the
National Kidney Foundation are to target a blood
pressure of 130/80 mmHg in diabetic patients.
2. Either an ACE inhibitor or an ARB should be
designated as the first line therapy given its
renoprotective effects that extend beyond blood
pressure lowering
42. Patients should adhere to a low sodium diet
The use of diuretics may also enhance the
antiproteinuric effects of RAAS inhibition while
simultaneously decreasing fluid overload and
HTN
The use of thiazide diuretics should be limited
to patients whose GFR is >40 mL/min, and
loop diuretics dosed at least twice daily are
more appropriate for patients whose GFR is
<40ml/min
43. Patients with diabetic nephropathy frequently require
additional antihypertensive drugs, and drugs may be
selected according to the comorbidity profile of an
individual patient.
Beta adrenergic antagonists may be indicated in patients
with arrhythmias, congestive heart failure, and coronary
artery disease
calcium channel blockers can be preferentially used in
patients that lack these conditions.
44. TAKE HOME MESSAGE
DIABETIC NEPHROPATHY is predictable on sequences
,hence renal biopsy is not indicated in cases of DN
40% of dialysis cases of ESRD are DN
45% of patients will have microalbuminuria after 5 to 10 yrs
of onset of type 1 DM
50% of these patients develop macroalbuminuria after 5 to
10 yrs after the development of microalbuinuria
50% of the cases of macroalbuminuria end up in ESRD will
need renal replacement therapy for survival
45. 90% of DM are type 2 and 10% are type 1
Hence cases of DN are from type 2
Microalbuminura or macroalbuminuria are detected at the
onset of type2 DM and after 5 yrs of diagnosis of type 1
Hence the estimation of albuminuria should be done at
the diagnosis of type 2 and 5yrs after diagnosis of type
1and repeat every 5 yrs if it is not detected
46. Type 1 diabetes mellitus is associated with Diabetic
retinopathy with macroalbuminuria in 90% of cases
But it is only 60% with type 2 DM
Once patient developes macroalbuminuria CKD is
irreversible
47. DIFFERENCE BETWEEN TYPE 1 AND 2 DM
1. micro or macro albuminuria may be present when type
2 dm is diagnosed ,reflecting its long asymptomatic
period
2. HTN mostly accompanies micro or macro albuminuria
In type 2 DM
3.microalbuminuria may be less predictive of DN and
progression to macroalbuminuria in type2
Albuminuria in type 2 may be secondary to factors
unrelated to DM. Example HTN, CHF,prostate
disease,infection.
