Contents

INTRODUCTION
DIABETIC NEPHROPATHY
PATHOPHYSIOLOGY
HISTOPATHOPHYSIOLOGY
CLINICAL PRESENTATION
TREATMENT
COMPLICATIONS
INTRODUCTION
• What is Diabetes?
WHO Definition
Diabetes is a chronic disease that occurs either when the pancreas does not
produce enough insulin or when the body cannot effectively use the insulin it
produces.

CDC(center for disease control) Definition

• Diabetes is a chronic(long lasting) health condition that affects how our body
turns food into energy.

ADA(American Diabetes Association) Definition

• Diabetes is a fasting plasma glucose level greater than or equal to 126 mg/dl
• Recent estimates indicate there are171 million people in the world with
diabetes in the year 2000 and this is projected to increase to 366 million by
2030.
• Diabetes is a condition primarily defined by the level of hyperglycaemia
giving rise to risk of microvascular damage (retinopathy, nephropathy and
neuropathy).
• It is associated with:
 Reduced life expectancy
Significant morbidity due to specific microvascular complications
Increased risk of macrovascular complications (ischaemic heart disease,
stroke and peripheral vascular disease)
Diminished quality of life.
Types of Diabetes
Type 1 diabetes
• is a chronic illness characterized by the body’s inability to produce insulin due
to the autoimmune destruction of the beta cells in the pancreas.
• Frequently occurs in childhood
Type 2 diabetes mellitus
• consists of an array of dysfunctions characterized by hyperglycemia resulting
from :
 resistance to insulin action
 inadequate insulin secretion
 excessive or inappropriate glucagon secretion.
 Type 2 diabetes usually develops in middle-aged people (over the age of 40)
and in later life.
Diabetic Nephropathy
• Diabetic nephropathy is a clinical syndrome characterized by the following :
Persistent albuminuria (>300 mg/d or >200 μg/min) that is confirmed on at
least 2 occasions 3-6 months apart
Progressive decline in the glomerular filtration rate (GFR)
Elevated arterial blood pressure.

• Diabetic nephropathy is the most common cause of nephrotic syndrome in

adults.
• Diabetic nephropathy is also the most common cause of end-stage renal disease
• It is the most common complication of Diabetes
Cont...
• Epidemiology
 As many as 50% of patients with DM of more than 20 years’ duration have
DN.
DN is responsible for about a third of cases of ESRD worldwide, and an even
larger fraction in the developed countries.
Worldwide, the prevalence of diabetes is projected to increase from 382
million in 2013, to over 592 million by 2035.
 This increase is projected to be sharpest in developed countries.
The prevalence of type 2 DM is particularly increasing due to the rising
prevalence of obesity worldwide.
Risk factors
• Not all patients with diabetes go on to develop diabetic nephropathy.
The main risk factors are:
 Modifiable
Poor control of blood glucose
High blood pressure
 Non-modifiable
A family history of diabetic nephropathy
Race (African Americans, Mexican Americans, and Pima Indians are at higher
risk).
Pathophysiology
• The disease progression of DN involves various clinical stages:
hyperfiltration, microalbuminuria, macroalbuminuria, nephrotic proteinuria to
progressive chronic kidney disease leading to end-stage renal disease (ESRD).
• The damage is exerted on all compartments of the kidney: the glomerulus, the
renal tubules, the vasculature and the interstitium.
• Renal fibrosis is the final common pathway of DN.
• This fibrosis is a product of multiple mechanisms including
 renal hemodynamic changes
 glucose metabolism abnormalities associated with oxidative stress as well as
inflammatory processes
 an overactive renin-angiotensin-aldosterone system (RAAS)

DN-Diabetic Nephropathy
Cont...
• The pathophysiology of diabetic nephropathy is thought to involve an interaction
between hemodynamic and metabolic factors.
• Hemodynamic factors include an increase in systemic and intraglomerular
pressure, as well as the over-activation of the RAAS.
• In the setting of diabetes, various factors stimulate the RAAS, which is one of the
most important pathways in diabetic nephropathy pathophysiology.
• Higher load of filtered glucose promotes upregulation of SGLT2 in the proximal
tubules, which cotransports sodium and glucose back into circulation.
• This leads to a decrease in the delivery of sodium chloride to the macula densa in
the distal tubules, promoting the release of renin and over-activating RAAS.
• Hyperfiltration is one of the earliest features of DN.
Cont...
• Several mechanisms have been proposed to cause hyperfiltration.
• One of these mechanisms is that as glomeruli becomes hypertrophied, filtration
surface area initially increases.
• Another possible mechanism is that abnormal vascular control in diabetic
nephropathy leads to a reduction in afferent glomerular arteriolar resistance and
an increase in efferent glomerular arteriolar resistance, leading to a net increase
in RBF and GFR.
• Glomerular hyperfiltration and an aberrant regulation of RAAS lead to
increased intraglomerular pressure, causing stress on the endothelial cells, the
mesangial cells and the podocytes.
• This exacerbates the dysfunction caused by the metabolic effects of
hyperglycemia.
Cont...
• Metabolic factors include the formation of Advanced glycation end-products
(AGEs), which have a central role in the pathophysiology of many of the
complications of diabetes mellitus, including cardiovascular complications.
• AGEs are chemical groups that form when a reducing sugar (glucose in this
case) reacts non-enzymatically with an amine group, predominantly lysine and
arginine, which are attached on proteins, lipids and nucleic acids.
• These glycation products accumulate on the proteins of vessel wall collagen,
forming an irreversible complex of cross-linked AGEs.

• An important way AGEs exert their effect is through a receptor-mediated

mechanism, most importantly by the receptor for advanced glycation end
products (RAGE).
Cont...
• RAGE is a signal transduction receptor found on a number of cell types including
macrophages, endothelial cells, renal mesangial cells and podocytes in the
glomerulus.
• Bindings of AGEs to RAGE receptors enhances production of cytosolic Reactive
Oxygen Species (ROS) as well as stimulates intracellular molecules such as Protein
Kinase C (PKC), NF-κB and the activation of growth factors TGF-B and vascular
endothelial growth factor (VEGF).
• These factors, along with the hemodynamic changes that occur, lead to podocyte
injury, oxidative stress, inflammation and fibrosis.
• As injury worsens, kidney function decreases and glomerular basement membrane
(GBM) become more permeable and less efficient at filtration.
• This is accompanied by a steady decline in kidney function
Histopathophysiology
• Three major histologic changes occur in the glomeruli of person with diabetic
nephropathy.
• First, mesangial expansion is directly induced by hyperglycemia, perhaps via
increased matrix production or glycation of matrix proteins.
• Second, thickening of the glomerular basement membrane (GBM) occurs.
• Third, glomerular sclerosis is caused by intraglomerular hypertension (induced by
dilatation of the afferent renal artery or from ischemic injury induced by hyaline
narrowing of the vessels supplying the glomeruli).
• The key change in diabetic glomerulopathy is augmentation of extracellular matrix.
• The earliest morphologic abnormality in diabetic nephropathy is the thickening of the
GBM and expansion of the mesangium due to accumulation of extracellular matrix
• Light microscopy findings show an increase in the
solid spaces of the tuft, most frequently observed as
coarse branching of solid material.
• Large acellular accumulations also may be
observed within these areas
knowen as kimmelstiel-Wilson lesions/nodules.

• Immunofluorescence microscopy may reveal

deposition of albumin, immunoglobulins, fibrin,
and other plasma proteins along the GBM in a
linear pattern, as a result of exudation from the
blood vessels.
• The renal vasculature typically displays evidence of
atherosclerosis, usually due to concomitant
hyperlipidemia and hypertensive arteriosclerosis.
 MC: mesangium
BM
Signs and symptoms
• The onset of symptoms is 5 to 10 years after the disease begins.
• A usual first symptom is frequent urination at night: nocturia.
• Other symptoms include:
 tiredness
 headaches
 a general feeling of illness
 nausea and vomiting,
 frequent daytime urination
 lack of appetite
 itchy skin, and leg swelling.
Clinical Presentation
• History
• Diabetic nephropathy should be considered in patients who have diabetes
mellitus (DM) and a history of one or more of the following:
Passing of foamy urine
Otherwise unexplained proteinuria
Diabetic retinopathy
Fatigue and foot edema secondary to hypoalbuminemia (if nephrotic syndrome
is present)
Other associated disorders such as peripheral vascular occlusive disease,
hypertension, or coronary artery disease
• Physical Examination
• Patients may have physical findings associated with long-standing diabetes
mellitus, such as:
Hypertension
Peripheral vascular occlusive disease (decreased peripheral pulses, carotid
bruits)
Evidence of diabetic neuropathy in the form of decreased fine sensations and
diminished tendon reflexes
Evidence of fourth heart sound during cardiac auscultation
Nonhealing skin ulcers/osteomyelitis
Treatment
•Glycemic control
•Management of Hypertension

•Dietary changes like restriction of dietary

proteins.
•Medication Summary
• Drug classes employed include:
hormones (ie, insulin), sulfonylureas, SGLT2
inhibitors, angiotensin-converting enzyme
(ACE) inhibitors, angiotensin receptor blockers
(ARBs), beta-adrenergic blocking agents,
calcium channel blockers, and diuretics.

-
Complications
• Renal complications of diabetic nephropathy include:
 increased risk of urinary tract infections(UTI)
 Serum electrolyte, water, and acid-base complications are also more common
in patients with diabetic nephropathy.