Transcript Diabetic nephropathy

Ian Gallen
Ian Gallen
 Over 40% of new cases of end-stage
renal disease (ESRD) are attributed to
diabetes.
 In 2001, 41,312 people with diabetes
began treatment for end-stage renal
disease.
 In 2001, it cost $22.8 billion in public
and private funds to treat patients
with kidney failure.
 Minorities experience higher than
average rates of nephropathy and
kidney disease
Incidence of ESRD
Resulting from Primary
Diseases (1998)
19%
3%
43%
12%
23%
Diabetes
Hypertension
Glomerulonephritis
Cystic Kidney
Other Causes
Stage 1: Hyperfiltration, or an increase in
glomerular filtration rate (GFR) occurs. Kidneys
increase in size.
Stage 2: Glomeruli begin to show damage and
microalbuminurea occurs.
Stage 3: Albumin excretion rate (AER) exceeds 200
micrograms/minute, and blood levels of creatinine
and urea-nitrogen rise. Blood pressure may rise
during this stage.
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Stage 4: GFR decreases to less than 75 ml/min, large amounts of protein
pass into the urine, and high blood pressure almost always occurs. Levels
of creatinine and urea-nitrogen in the blood rise further.
Stage 5: Kidney failure, or end stage renal disease (ESRD). GFR is less than
10 ml/min. The average length of time to progress from Stage 1 to Stage 4
kidney disease is 17 years for a person with type 1 diabetes. The average
length of time to progress to Stage 5, kidney failure, is 23 years.
Ian Gallen
 Major
cause of early death in DM
 Major cause of amputation
 RRT is arduous for the patient and
expensive
 Nephropathy is largely avoidable (or can
be delayed)
 Local performance is poor compared
with national data
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 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
Ian Gallen
Ian Gallen
 Nephropathy
in type Type 1 diabetes
• Nearly always due to hyperglycaemia
• Strong genetic predisposition
 Nephropathy
in T2DM
• More common
• May be due to hyperglycaemia
• But often due to other causes particularly
inflammation
• Frequently multi-factorial
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Results from hyperglycemia, advanced glycosylation products, and activation of cytokines.
Inflammatory medium, resulting in activation of the innate immune system, which results in
activation of the nuclear transcription factors-kappa B (NF-κB), and release of inflammatory
mediators, including, interleukin (IL)–1β and tumor necrosis factor (TNF)–α.
Hyperglycemia also increases the expression of transforming growth factor-β (TGF-β) in the
glomeruli and of matrix proteins, specifically stimulated by this cytokine. TGF-β and vascular
endothelial growth factor (VEGF) may contribute to the cellular hypertrophy and enhanced
collagen synthesis and may induce the vascular changes observed in persons with diabetic
nephropathy.
Hyperglycemia also may activate protein kinase C, which may contribute to renal disease and
other vascular complications of diabetes.
Familial or perhaps even genetic factors also play a role. Certain ethnic groups, particularly
African Americans, persons of Hispanic origin, and American Indians, may be particularly
disposed to renal disease as a complication of diabetes.
Some evidence has accrued for a polymorphism in the gene for angiotensin-converting
enzyme (ACE) in either predisposing to nephropathy or accelerating its course.
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Mesangial expansion is directly induced by hyperglycemia,
perhaps via increased matrix production or glycosylation of
matrix proteins.
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Thickening of the glomerular basement membrane (GBM)
occurs.
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Glomerular sclerosis is caused by intraglomerular
hypertension
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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.
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Ian Gallen
Ian Gallen
A and B Glomerulus showing only mild
ischemic changes
C, D Class II glomeruli with mild and
moderate mesangial expansion,
respectively.
E and F Kimmelstiel–Wilson lesion.
G is an example of glomerulosclerosis that
does not reveal its cause
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 Light-Chain
Deposition Disease
 Multiple Myeloma
 Nephritis, Interstitial
 Nephrosclerosis
 Nephrotic Syndrome
 Renal Artery Stenosis
 Renal Vein Thrombosis
 Renovascular Hypertension
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Urinalysis
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Persistent albuminuria (>300 mg/d or >200 μg/min) that is confirmed on at least 2
occasions 3-6 months apart
Blood Tests
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Serum and Urinary Electrophoresis
 Serum and urinary electrophoresis is performed mainly to help exclude multiple myeloma (in
the appropriate setting) and to classify the proteinuria (which is predominantly glomerular in
diabetic nephropathy).
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Renal Ultrasonography
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Renal Biopsy
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Observe for kidney size, which is usually normal to increased in the initial stages and, later,
decreased or shrunken with chronic renal disease. Rule out obstruction.
Renal biopsy is not routinely indicated in all cases of diabetic nephropathy, especially in
persons with a typical history and a progression typical of the disease. It is indicated if the
diagnosis is in doubt, if other kidney disease is suggested, or if atypical features are
present.
Histologic Findings
Mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix
production or glycosylation of matrix proteins.
• Thickening of the glomerular basement membrane (GBM) occurs.
• Glomerular sclerosis.
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Ian Gallen
 Salt
restriction
• Reducing dietary salt intake to less than 5-6 g/d
and phosphorus and potassium restriction in
advanced cases.
 Weight
loss
 Bariatric surgery
 Smoking Cessation
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In persons with either type 1 or type 2 diabetes mellitus (DM),
hyperglycemia has been shown to be a major determinant of the
progression of diabetic nephropathy. The evidence is best
reported for type 1 DM.
Intensive therapy can partially reverse glomerular hypertrophy
and hyperfiltration, delay the development of microalbuminuria,
and stabilize or even reverse microalbuminuria.
Pancreatic transplant recipients in whom true euglycaemia is
restored suggest that strict glycaemic and metabolic control may
slow the progression rate of progressive renal.
Intensive blood glucose control in patients with type 2 DM
significantly increased treatment costs but substantially reduced
the cost of complications and increased the time free of
complications.
Kidney Int. Jun 1995;47(6):1703-20. [Medline].
Lancet. Sep 12 1998;352(9131):837-53. [Medline].
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Sitagliptin-Approximately 80% of sitagliptin is cleared by the kidney;
therefore, the standard dose of 100 mg daily should be reduced in
patients with reduced glomerular filtration rates (GFRs). With an
estimated GFR (eGFR) of 30 or greater to less than 50 mL/min/1.73 m2, the
recommended dose is 50 mg once daily, and with an eGFR less than 30
mL/min/1.73 m2, a dose of 25 mg once daily is advised.
Saxagliptin is 2.5-5 mg daily in patients with an eGFR greater than 50
mL/min, but dose adjustment is recommended in patients with an eGFR of
50 mL/min/1.73 m2 or less to 2.5 mg daily.
Alogliptin also requires a dose reduction from 25 mg daily to 12.5 mg
daily in patients with an eGFR of less than 60 mL/min/1.73 m2 and to 6.25
mg daily if the eGFR is less than 30 mL/min/1.73 m2.
Linagliptin-no dose adjustment is necessary in patients with a reduced
GFR.[21]
Diabetes Care. Jul 2007;30(7):1862-4.
Expert Opin Drug Metab Toxicol. May 2013;9(5):529-50.
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 Canagliflozin
• dose in patients with an eGFR of 45 to less than 60
mL/min/1.73 m2 is 100 mg once daily and it is not
recommended in patients with an eGFR of less than
45 mL/min/1.73 m2.
 Dapagliflozin
• not recommended in patients with an eGFR of less
than 60 mL/min/1.73 m2.
 Empagliflozin
• eGFR of 45 to less than 60 mL/min/1.73 m2 is 100 mg
once daily and it is not recommended in patients
with an eGFR of less than 45 mL/min/1.73 m2.
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Exenatide clearance is GFR dependent and is reduced at low
GFRs.
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GLP1 should be used with caution in patients with a GFR of 30-50
mL/min and not be used at all if the eGFR is less than 30 mL/min.
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Liraglutide is not metabolized by the kidney, and no dose
adjustment is necessary in patients with a decreased GFR,
including ESRD, although data in this population are limited.
ABCD audit shows Liraglutide safe and effective with eGFR>30
mL/min
Br J Clin Pharmacol. Sep 2007;64(3):317-27.
Endocr Pract. May-Jun 2011;17(3):345-55.
Practical Diabetes 2013; 30(2): 71–76
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Progression of kidney disease is best achieved with a blood pressure control.
Long-term treatment with ACE inhibitors, usually combined with diuretics, reduces blood
pressure and albuminuria and protects kidney function in patients with hypertension, type 1
DM, and nephropathy.
ACE inhibition has been shown to delay the development of diabetic nephropathy.
The beneficial effect of ACE inhibition on preventing progression from microalbuminuria to
overt diabetic nephropathy is long-lasting (8 y) and is associated with the preservation of a
normal glomerular filtration rate (GFR).
Treatment with an ACE inhibitor for 12 months has significantly reduced mean arterial blood
pressure and the urinary albumin excretion rate in type 2 DM patients who have
microalbuminuria.
ACE inhibitors are superior to beta-blockers, diuretics, and calcium channel blockers in
reducing urinary albumin excretion in normotensive and hypertensive type 1 and type 2 DM
patients.
In addition to beneficial cardiovascular effects, ACE inhibition has also been demonstrated to
have a significant beneficial effect on the progression of diabetic retinopathy and on the
development of proliferative retinopathy.
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RENAALStudy and IDNT demonstrated that angiotensin II receptor
blockers (ARBs) are superior to conventional therapy and amlodipine in
slowing the progression of overt nephropathy.
No head-to-head comparison of ACE inhibitors and ARBs is availible.
MICRO-HOPE, ramipril reduced the risk for myocardial infarction, stroke,
or cardiovascular death by 26% after 2 years.
Combined treatment with ACE inhibitors and ARBs significantly
decreased blood pressure, proteinuria, and rate of change of reciprocal
serum creatinine
however, higher cardiovascular death was reported among the olmesartan-treated patients
compared with placebo. Hyperkalemia was more frequent in the olmesartan–treated group
than in the placebo group.
• Nephron-D trial, which evaluated the effect of adding losartan, an ARB, to the ACE inhibitor
lisinopril on albumin-to-creatinine ratio in 1448 patients with type 2 diabetes was stopped
early because of safety concerns.
• Combination therapy significantly increased the risk of hyperkalemia and acute kidney
injury.
• Thus, the combination should be avoided as a strategy to reduce proteinuria with the hope
of slowing progression of diabetic nephropathy, and should be reserved for individual
situations in which optimal control of blood pressure may require it.
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 Endothelin
antagonists have
demonstrated antifibrotic, antiinflammatory, and antiproteinuric effects
in experimental studies.
 Avosentan administered in addition to
standard treatment with an ACE inhibitor
or an ARB, reduced the mean relative
urinary albumin excretion rate (-16.3% to
-29.9%, relative to baseline).
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Efforts should be made to modify and/or treat
associated risk factors such as hyperlipidemia,
smoking, and hypertension.
 Specific goals for prevention include the following:
 Optimal blood glucose control (hemoglobin A1c
[HbA1c] < 7%)
 Control of hypertension (BP < 120/70 Hg)
 Avoidance of potentially nephrotoxic substances
such as nonsteroidal anti-inflammatory medications
and aminoglycosides
 Early detection and optimal management of
diabetes, especially in the setting of family history of
diabetes
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Does the patient have any symptoms or do they feel completely well?
Diabetic nephropathy is commonly a completely asymptomatic condition until the patient has quite
advanced renal impairment and it is therefore essential that annual screening by measuring Us and Es
and performing urinalysis for microalbuminuria are undertaken.
How long has the patient had diabetes?
In general, the longer the patient has had diabetes the greater the risk of complications although this
is is a very approximate guide and it is certainly possible to have had diabetes for only a few years
and already developed complications (especially so for T2DM).
Conversely, some patients can have diabetes for many decades and develop few or any
complications.
Does the patient have other microvascular complications?
The presence of other microvascular complications such as retinopathy and neuropathy increases the
odds that the patient will also develop nephropathy, but this is only a rule of thumb and it certainly
shouldn't be inferred that patients without other microvascular complications cannot, or will not
develop nephropathy.
How good has the glycaemic control been over the years?
If there is a long history of poor glycaemic control with chronically high HbA1c then development of
microvascular complications such as nephropathy is more likely than if control has generally been
very good.
Has the patient been feeling non specifically unwell, experiencing pruritus, anorexia and
weight loss?
These may be symptoms of uraemia, but the renal impairment should normally be picked up long
before the patient develops these symptoms by the deterioration on the annual eGFR.
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 It
is essential to ensure that a patient with
deteriorating renal function is not on
potentially nephrotoxic drugs such as
non steroidal anti inflammatory agents.
 If there has been a sudden step-wise
deterioration in renal function check
changes in medication or X-ray contrast
invsetigations
 eGFR is <30 ml/min, metformin therapy
should be withdrawn.
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 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
 Beta-blockers
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Glycaemic targets
Inidividualised targets should be set with each patient.
A target of 6.5% (48 mmol/mol) without experiencing unacceptably frequent
hypoglycaemia is a realistic aim.
However, for a 75-year-old patient with a ten-year history of T2DM and an HbA1c of 9% (75
mmol/mol), attempting reduction to 6.5% (48 mmol/mol) will probably confer no
survival advantage and may even increase mortality rate as shown by the recent
ADVANCE, ACCORD and VADT trials.
Caution in the elderly and those with frequent hypoglycaemia and hypoglycaemia
unawareness and those who have had diabetes for many decades and have developed
autonomic neuropathy, gastroparesis and other comorbidity that render coping with
hypoglycaemia especially difficult.
Blood pressure targets
Control of blood pressure has been shown to be an effective way of reducing the risk of
nephropathy.
Use ACE inhibitors or angiotensin receptor blockers (ARBs) first.
NICE recommends BP<140/80 mm Hg for people.
ACCORD-BP study that in patients with T2DM who are at increased cardiovascular risk, BP
lowering to target <120/80 conferred no survival benefit and some increased risk.
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Urine dipstick analysis
Detect overt proteinuria, haematuria and infection. Haematuria is not a
normal feature of diabetic nephropathy and its presence should alert the
physician to the possibility of an alternative diagnosis.
ACR
Values of <3 are normal and >3, especially if persistent, may indicate
early nephropathy
Renal ultrasound scan
Assessing renal size and ruling out obstruction or other structural lesions are
important steps in making a diagnosis of diabetic nephropathy.
What other investigations should be arranged?
1. Urinalysis to screen for haematuria and if haematuria is present (in the
absence of infection) then urinary microscopy should be performed to
look for other features of active sediment such as casts. If these are
present, they indicate a glomerular lesion such as glomerulonephritis.
2. Other blood tests such as protein strip, immunoglobulins, complement
levels, CRP, ESR, calcium and auto-antibodies if there are clinical
indications to do these.
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 Check
your practice systems for all patients
with DM and EgFR<45
 See if those patients are already known to
renal team
 Review all medications
 Review investigations
 If not clear that it is diabetic nephropathy,
refer
 For all, put care planning goals for
glycaemic control, blood pressure, lipids,
smoking and weight.
 Review peripheral pulses and refer
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There are three primary treatment
options for individuals who experience
ESRD:
1. Hemodialysis
2. Peritoneal Dialysis
3. Kidney Transplantation
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 Procedure
• A fistula or graft is created to access the
bloodstream
• Wastes, excess water, and salt are removed from
blood using a dialyzer
• Hemodialysis required approx. 3 times per week,
each treatment lasting 3-5 hrs
• Can be performed at a medical facility or at
home with appropriate patient training
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 Hemodialysis
Diet
• Monitor protein intake
• Limit potassium intake
• Limit fluid intake
• Avoid salt
• Limit phosphorus intake
 Complications
• Infection at access site
• Clotting, poor blood flow
• Hypotension
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 Procedure
• Dialysis solution is transported into the abdomen
through a permanent catheter where it draws
wastes and excess water from peritoneal blood
vessels. The solution is then drained from the
abdomen.
• Three Types of Peritoneal Dialysis
 Continuous Ambulatory Peritoneal Dialysis (CAPD)
 Continuous Cycler-Assisted Peritoneal Dialysis
(CCPD)
 Combination CAPD and CCPD
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 Peritoneal
Dialysis Diet
• Limit salt and fluid intake
• Consume more protein
• Some potassium restrictions
• Reduce caloric intake
 Complications
• Peritonitis
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 Procedure
• A cadaveric kidney or kidney from a related or
non-related living donor is surgically placed into
the lower abdomen.
• Three factors must be taken into consideration to
determine kidney/recipient match:
 Blood type
 Human leukocyte antigens (HLAs)
 Cross-matching antigens
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 Kidney
Transplant Diet
• Reduce caloric intake
• Reduce salt intake
 Complications/Risk
Factors
• Rejection
• Immunosuppressant side effects
 Benefits
• No need for dialysis
• fewer dietary restrictions
• higher chance of living longer
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 Maintain
blood pressure <130/80 mm/Hg
 Maintain preprandial plasma glucose 90130 mg/dl
 Maintain postprandial plasma glucose
<180 mg/dl
 Maintain A1C <7.0%
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American Diabetes Association: Nephropathy in Diabetes (Position
Statement). Diabetes Care 27 (Suppl.1): S79-S83, 2004
National Kidney and Urologic Diseases Information Clearinghouse.
Kidney Disease of Diabetes. Bethesda, MD: National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of
Health (NIH), DHHS; 2003.
United States Renal Data System. USRDS 2003 Annual Data
Report. Bethesda, MD: National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of Health (NIH), DHHS;
2003.
DeFronzo RA: Diabetic nephropathy: etiologic and therapeutic
considerations. Diabetes Reviews 3:510-547, 1995
National Kidney and Urologic Diseases Information Clearinghouse.
Kidney Failure: Choosing a Treatment That’s Right For You.
Bethesda, MD: National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health (NIH), DHHS; 2003.
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