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Diabetic Nephropathy:
“You can't cure it so you have
to endure it”
BY DR.KARTHIK.RAO.N
Current Terminology
• Kidney, not Renal (or Reno)
• CKD, not CRF
• DKD (= diabetic nephropathy)
• AKI, not ARF
• Still ESR...
Definition of CKD
Structural or functional abnormalities of
the kidneys for >3 months, as manifested
by either:
1. Kidney ...
Definition and Problem
• Progressive in UAE a/w BP and GFR
• 35-50% DN in Type 1 after 20 years of disease
• 10- ? 20% DN ...
Stages of Chronic Kidney Disease
Stage Description
GFR
(mL/min)
1
Kidney damage
normal or GFR
≥90
2
Kidney damage
mild GFR...
Stages of Diabetic Nephropathy
• Hyperfilteration
• Stage of Clinical Latency
• Incipient Nephropathy
• Overt Nephropathy
...
Diagnosis
Hyperfiltration
Clinical Latency
Microalbuminuria
Macroalbuminuria
Renal failure
Diabetes
Microalbuminuria
Dipst...
Stage of
hyper-
filtration
Micro
albumi-
nuria
Macro
albumi-
nuria
Azotemia
(Renal
failure)
End stage
Renal
disease
Normo
...
Natural History
Type II
Microalbuminuria
Macroalbuminuria
Renal failure
Diagnosis
Perkins BA, Et al. N Engl J Med 2003;348:2285-93.
Diagno...
Definitions of abnormalities in albumin
excretion
Because of variability in urinary albumin excretion, two of three specim...
Type II
Macroalbuminuria
Renal failure
Diagnosis
Perkins BA, Et al. N Engl J Med 2003;348:2285-93.
Diagnosis
Hyperfiltrati...
Type II
Renal failure
Diagnosis
Perkins BA, Et al. N Engl J Med 2003;348:2285-93.
Diagnosis
Hyperfiltration
Clinical Laten...
Microalbuminuria & Proteinuria
Normal Microalbuminuri
a
Overt
proteinuria
F M F M
Albumin/creatinine
ratio (mg/mmol)
<3.5 ...
U/A at Diagnosis
(Type 2 patients)
Random spot collection
Albumin:creatinine
Repeat 3x in 3-6 months
2 of 3
≥ 30mg/g
creat...
16
What are Diabetics with Nephropathy Dying
From?
Stroke
Myocardial
Infarction
Heart
Failure
Sudden
Death
Risk Factors : Non Modifiable
• Race: Indo-Asians, Africans, Hispanics, Native Americans.
• Familial clustering:
In Type 1...
Risk factors: Modifiable
• Hypertension
• Dyslipidemia
• Smoking
• Poor glycemic control
• Obesity
• Oral Contraceptives
•...
Natural History in Type 2 DM
• GFR decline once proteinuria present 12
ml/min/year untreated
• Patients often die of other...
Hypertension
• Greater than 140/90 increases the risk of
diabetes
• 50-60% of newly diagnosed patients also
have HTN at di...
Undesirable lipid levels
• HDL less than 35 mg/dL
• Triglycerides greater than 150 mg/dL
• Think diabetes or hypothyroidis...
Predictors of progression
• In normoalbuminuric person
• Glycemic control
• In established DN
• Hypertension
• Degree of p...
• Hyperglycaemia
Early histological lesions reversible
with normoglycaemia
• Hypertension
Predicts microalbimunuria,
prote...
Oparil et al. Ann Intern Med 139:761-76, 2003.
ANG II ANG II
Cross-talk between the Insulin and Aangiotensin- II
Angiotensin II insulin
sensitivity & insulin
secretion, explaining
the...
Treatment
1. Glycemic control
2. Blood pressure control
3. Angiotensin 2 control
4. Proteinuria control
5. Cholesterol con...
DCCT
1400 T1DM
Intensive Conventional
HbA1C 7.3% 9.1%
Reduction in
Retinopathy- 47%
Microalbumnuria- 39%
Clinical Nephropa...
Strict glycemic control prevents microalbuminuria in patients with
type 1: 2.2%/year DN in Intensive and 3.4% in conventio...
Randomized prospective trial of
treatment strategies in type II diabetes
ukpdsType 2 diabetic patients 5,102
Person years ...
Benefits of Glycemic Control
•Delay the development of albumin excretion
•Stabilize or protein excretion in pts with UAE
•...
ACEi are good
ARB are good
What about both together?
33
Ang I
Ang II
Progressive Diabetic Nephropathy
ACE
Renal Injury
and Proteinuria
ACEi
AT1 Receptor
Non-ACE
Pathways
Aldos...
CALM Study
• N= 200
• Type II DM with
microalbuminuria
• Randomized to:
• Lisinopril 20 mg qd
• Candesartan 16 mg qd
• Com...
Calcium channel blockers
• Verapamil does not delay
development of microalbuminuria
• Verapamil does reduce proteinuria
in...
ARBs: Evolution of protective benefits
↓BP
↓Stroke
↑Glycemic control
↓Heart failure
↓Renal dysfunction
↓CHD (?)
ONTARGET
• Telmisartan (16.7%) noninferior; combination
(16.3%) not superior to ramipril (16.5%) for
primary endpoint (CV ...
RENIN INHITORS
PLUS ARBS/ACEI
Aliskiren Trial in Type 2 Diabetes Using
Cardio-Renal Endpoints (ALTITUDE):
• To determine whether aliskiren 300 mg once
d...
Treatment
 Blood pressure control
 Glycemic control
3. Proteinuria control
4. Cholesterol control
Protein restriction slows
progression of DN
Is Anemia Causing Cardiovascular
And Renal Disease In Diabetics,
Or is it Just A Marker?
Hypothesis: Anemia is an Important CV Risk
Factor in Chronic Kidney Disease
Chronic Kidney
Disease
Cardiovascular disease
...
< 2 % pts of DRD require RRT because others often
die of CVD before reaching ESRD.
Dialysis
Get an early vascular access f...
How Should We Manage Patient
With Diabetic Nephropathy Today?
Parameter
• Lower BP……………
• Block RAAS……
• Improve glycemia ...
Conclusions
• Diabetic nephropathy is
the most common
cause of ESRD in the
world
• ESRD is a rare out-
come among diabetic...
Key messages
• Screening for diabetic renal disease is easy and should
be performed annually
• Good glycaemic control is t...
Diabetic Nephropathy
Over 40% of new cases of
end-stage renal disease
(ESRD) are attributed to
diabetes.
In 2001, 41,312...
Five Stages of Kidney Disease
Stage 1: Hyperfiltration, or an increase in
glomerular filtration rate (GFR) occurs. Kidneys...
Investigations
Urinary Protein assessment
Dipstick
24hour urinary protein estimation
Albumin: Creatinine ratio > 2.5 in ma...
Five Stages of Kidney Disease
(con’t.)
Stage 4: GFR decreases to less than 75 ml/min, large
amounts of protein pass into t...
Screening for Diabetic
Nephropathy
Test When Normal Range
Blood
Pressure1
Each office visit <130/80 mm/Hg
Urinary
Albumin1...
Treatment of Diabetic
Nephropathy
• Hypertension Control - Goal: lower blood
pressure to <130/80 mmHg
– Antihypertensive a...
• Glycemic Control
– Preprandial plasma glucose 90-130 mg/dl
– A1C <7.0%
– Peak postprandial plasma glucose <180
mg/dl
– S...
Treatment of End-Stage Renal
Disease (ESRD)
There are three primary treatment
options for individuals who experience
ESRD:...
Hemodialysis
• Procedure
– A fistula or graft is created to access the
bloodstream
– Wastes, excess water, and salt are
re...
• Hemodialysis Diet
– Monitor protein intake
– Limit potassium intake
– Limit fluid intake
– Avoid salt
– Limit phosphorus...
Peritoneal Dialysis
• Procedure
– Dialysis solution is transported into the
abdomen through a permanent catheter
where it ...
Peritoneal Dialysis (cont.)
• Peritoneal Dialysis Diet
– Limit salt and fluid intake
– Consume more protein
– Some potassi...
Kidney Transplant
• Procedure
– A cadaveric kidney or kidney from a related
or non-related living donor is surgically
plac...
How Can You Prevent
Diabetic Kidney Disease?
• Maintain blood pressure <130/80 mm/Hg
• Maintain preprandial plasma glucose...
63
Albuminuria then Proteinuria
• Microalbuminuria first (lower MW)
– Raised by GFR (i.e. BSL, protein diet,
fever, exerci...
64
Diabetic Nephropathy
• From haemodynamic & metabolic
stresses
• Metabolic stress
– deposition of advanced glycosylation...
65
Nephropathy Risk Factors
• DM Type & Duration
– 20% of Type I after 20 years
– 40% of Type II any duration
• Poor diabe...
66
• 1st clinical sign is microalbuminuria (ACR)
• Kidney not able to catabolise albumin
• This can also occur transient...
67
Nephropathy Risk Factors
• DM Type & Duration
– 20% of Type I after 20 years
– 40% of Type II any duration
• Poor diabe...
68
Nephropathy Risk Factors
• Modifiable
– HbA1c, BP & total cholesterol (Odds Ratio 43)
– Obesity, smoking
• Non-modifiab...
69
Delaying Complications
• Tight diabetic control
– Prevention of microvascular Cmplx
• Risk of hypos
• Tight BP control
...
70
ACE Inhibitors can prevent
progression of renal failure
120
160
200
240
280
320
350
400
80
0 1 2 3 4 5 6
Years
Ann Inte...
71
ACEI/ARB Proteinuria
Remission
H
L
H
L
30
40
50
60
70
80
90
2000
Jan 2000
2001 2002
Creatinine - Plasma
umol/L
H
0
500
...
72
Q. Which features are typical of
diabetic CKD at presentation ?
• Haematuria NO
• Small scarred kidneys NO
• Progress t...
73
Diabetes and ESKD
• Reducing insulin requirements
• Difficult vascular access
• Accelerated macrovascular disease
• Adv...
74
How can DM effect Dialysis?
• Autonomic neuropathy – may suffer hypotension
increased by large fluid shift in HD
• Unco...
75
Strict BSL Control in early Type I
• Target HbA1c < 7%
• For every 1% HbA1c:
– 10% CVD
– 40% Microvascular Cmplx
• BUT:...
76
Strict BSL Control in DM CKD
• AND:
• Minimal benefit if overt proteinuria
• Diabetes “cured” by advancing CKD
– reduce...
77
Metformin in CKD
• No hypos or weight gain
• Inexpensive
• BUT:
– Renally-excreted
– Excess doses anorexia, diarrhoea
–...
78
Glitazones in DM
• Av.1% fall in HbA1c as monoRx or add-on
• Preserves beta-cell fn - use early
• Durable effect >3yrs
...
79
Strict BP Control at any stage
• ½’s (or even stops) rate of fall in GFR
• Greater benefit than tight BSL control
• Fal...
80
Use of ACEi/ARBs: actions
• Antihypertensive
– by salt excess, by thiazides
– need mean of 3 agents in mild CKD
• Antip...
Creatinine- it’s the best we
have!
Rough GFR
 Equations should be
used only in the steady
state
 Not useful in ARF
 Reasonable criteria
◦ CrCl> 50ml/min
◦...
Natural history of DN
Diabetes
1,2 3 4 5
Time
GFR
Creat
Problems
 Precautions
 Blood pressure control
 Dietary protein restriction
 Management of MBD
 Management of anemia
...
Precautions
 No nephrotoxics
◦ Impair glomerular function: NSAIDS
◦ Impair tubular function: Aminoglycosides
◦ NO contras...
Blood pressure management
Systemic BP reduction Intra-glomerular BP reduction
Anti-proteinuric effect
Blood pressure contr...
Protein restriction
 Preservation of organ repair
 Daily dietary requirement (FAO)
◦ 0.6 g/Kg/d plus 2 SD= 0.8 g/Kg/d
 ...
Secondary
hyperparathyroidism
89
90
Decreased GFR
Hyperphosphatemia
Hypocalcemia
Low vitamin D
+
decreased activation
+
Resistance
Secondary hyperparathyro...
91
Decreased GFR
Hyperphosphatemia
Hypocalcemia
Low vitamin D
+
decreased activation
+
Resistance
Secondary hyperparathyro...
Diabetic Nephropathy
 DN occurs in 35-40% of patients with type I
diabetes (IDDM) whereas it occurs only in
15-20% of pat...
BMD
 Dietary phosphate
restriction
 Phosphate binders
◦ Aluminium
◦ Calcium
◦ Magnesium
◦ Non aluminium,
calcium, magens...
Anemia management
EPO deficiency
Defect in iron absorption
B12 and folate
deficiency
Diseases like myeloma
Hyperparathyroi...
Correction of anemia
 Identify iron
deficiency
 Oral iron vs
parenteral iron
 Iron sucrose
 Don’t overload iron
 Avoi...
Vaccinations
 Hepatitis B
◦ 20 mcg each deltoid IM 0, 1, 2, 6 months
◦ Check Anti HBS titre post vaccination
after 3rd do...
Volume control
 Problems with salt and water excretion
in CKD is relatively later
 Proteinuric conditions may develop
th...
Diabetes
 Asymptomatic bacteriuria is more common
(20%)
 UTIs are likely to be more severe in diabetic
than nondiabetic ...
Diabetic Nephropathy
A clinical syndrome
DM +
Persistent albuminuria, Worsening
proteinuria, Hypertension &
progressive re...
Diabetic nephropathy (DN) is a major
cause of ESRD, and the incidence of
diabetes
mellitus is rising rapidly.
Diabetic Nephropathy
 DN occurs in 35-40% of patients with type I
diabetes (IDDM) whereas it occurs only in 15-
20% of pa...
Effect of Angiotensin Blockade
Afferent arteriole
Efferent arteriole
Glomerular pressure
( GFR)
Glomerulus
Bowman’s Capsul...
Irbesartan in patients with type 2 diabetes &
microalbuminuria study
 590 NIDDM patients with HTN and
microalbuminuria wi...
ARBs in NIDDM,HTN & microalbuminuria-Parving 2001
D.N.-Management
 ACEI or AII RB- in both expt & human
Reduce glomerular hypertension
Reduce proteinuria independent of
...
DN: ADA Position Statement
Screening:
Perform an annual test for the presence of microalbuminuria in
1) type 1 diabetic pa...
UK Prospective Diabetes Study (UKPDS) Major Results:
Powerful Risk Reductions
Better blood pressure control reduces…
 Str...
National Kidney Foundation Recommendations on
Treatment of HTN and Diabetes
 Blood pressure goal: 130/80 mmHg
 Target bl...
Treatment Objectives to Prevent Macrovascular
Disease in Diabetic Patients
 Hypertension
◦ BP < 130/80 mmHg
 Hypercholes...
Management of HTN and Chronic Renal Disease (CRD)
in Diabetics
 Reduce BP to <130/80 mmHg
 Use multiple antihypertensive...
Diabetic Nephropathy
Clinical syndrome characterised by
persistent albuminuria (>300mg/24hrs)
on at least 2 occasions sepa...
Epidemiology
Incidence of Diabetic Nephropathy in
Type 1 Diabetes
4-17% 20 years
16-30% 30 years
30-40% 40 years
Epidemiology
Incidence of Diabetic Nephropathy in
Type 2 Diabetes
5% at diagnosis
20% after 20 years
Screening for Microalbuminuria
Albumin excretion increased due to
 Strenuous exercise
 Oral Protein intake
 Urinary inf...
Urinary Albumin Excretion
Rates
Normoalbuminuria < 30mg/day
Microalbuminuria 30-300mg/day
Overt Nephropathy > 300mg/day
Screening for Microalbuminuria
Type 1: Yearly after 5 years of diagnosis
Type 2: Annually from diagnosis
Protein Kinase C
Renal injury due to hyperglycaemia increase
reactive oxygen species.
Activation of PK C and TGF b results...
Inhibition of PKC by
Ruboxistaurin in Rats
 Reduces Glomerular Hyperfiltration
 Albuminuria
 Extra cellular Matrix accu...
Mechanisms for the Renoprotective
Effect of ACE Inhibitors
 Lower Systemic Blood Pressure
 Lower Intra glomerular Pressu...
Mechanisms for the Renoprotective
Effect of ACE Inhibitors
Inhibit non Heamodynamic effects of
Angiotensin on various cell...
Mechanisms for the Renoprotective
Effect of ACE Inhibitors
Reduction in Oxidative Stress
Inhibit macrophage activation,
pr...
Renal preglomerular vasodilation
Systemic hypertension
Glomerular hypertension
Glomerular sclerosis
Hyperglycemia
Genetic ...
Renal preglomerular vasodilation
Systemic hypertension
Glomerular hypertension
Glomerular sclerosis
Hyperglycemia
Genetic ...
Blood pressure management
Systemic BP reduction Intra-glomerular BP reduction
Anti-proteinuric effect
Blood pressure contr...
Treatment
• Hypertension control:
– Lower the BP, slower the decline in GFR in patients with diabetic
nephropathy
– JNC VI...
Role of Aldosterone in the Pathogenesis
of Diabetic Nephropathy
Treatment
• ACE inhibitors:
– Type I diabetes with nephropathy: captopril vs. placebo
– 50% RR of combined end points of d...
Treatment
• Angiotensin-receptor blockers:
– RENAAL study(2001)
• 1513 pts with type II DM and nephropathy. Losartan vs. p...
Renal preglomerular vasodilation
Systemic hypertension
Glomerular hypertension
Glomerular sclerosis
Hyperglycemia
Genetic ...
Diabetic Nephropathy:
Important Message
• Lower blood pressure < 130 / 80 mmHg
• Reducing Proteinuria
• Inhibition of Reni...
ACEi- or ARB-Based Regimens for Diabetic
Nephropathy Do Not Go Far Enough!
Diabetic Nephropathy: Important Message
• Small short-term studies suggest combinations of
ACEi and ARB reduce proteinuria...
Secondary hyperparathyroidism
Abnormalities in metabolism of calcium and phosphorus in patients with chronic kidney disease
Targets
Stage Calcium* Phosphorous PTH
Stage 3 8.4 to 9.5 2.7 to 4.6 35-70
Stage 4 8.4 to 9.5 2.7 to 4.6 70-110
Stage 5 8....
BMD
• Replenishment of vitamin D stores
• Activated vitamin D 1, 25 (OH)2D3
• Vitamin D analogues
– Paricalcitrol
– Doxerc...
Anaemia
• May occur when GFR < 50 % & almost always present
when GFR < 30 %
• Correct deficiencies
– Iron, Folic acid, Vit...
Vaccinations
• Hepatitis B
– 20 mcg each deltoid IM 0, 1, 2, 6 months
– Check Anti HBS titre post vaccination after 3rd do...
Fluid management
Many diabetics have nephrotic state and severe
edema and need rigorous salt & fluid restriction
• Severe ...
Cardiovascular disease screen
• Renal disease is a cardiovascular risk factor
• CKD promotes vascular calcification
• Non ...
Options of renal replacement
• Hemodialysis
• Peritoneal dialysis
• Renal transplantation
Peritoneal dialysis
Advantages
• Slow, gentle
• Round the clock clearance
• Greater salt, fluid and dietary
freedom
• Mobi...
Others
• Lipid lowering - diet, statins
• Low dose aspirin
• Avoid nephrotoxic drugs & contrast procedures
• Prevent & tre...
Diabetic Nephropathy: Some Novel
Therapies Under Investigation
• Pirfenidone –antifibrotic agent
• Aliskerin anti-renin ag...
Recommendations:
Nephropathy treatment (1)
• Nonpregnant patient with micro- or macroalbuminuria
– Either ACE inhibitors o...
Control blood sugars: which drug
to use ?
• Drugs contraindicated: Metformin
• Preferably not used: Glibenclamide,
Chlorpr...
Blood pressure management
 Preferred drugs:
Angiotensin receptor blocker
ACE inhibitor
Non DHP calcium channel blocker: D...
Recommendations:
Nephropathy treatment (2)
• In patients with type 1 diabetes, hypertension, and any
degree of albuminuria...
Recommendations:
Nephropathy Treatment (4)
• Reduction of protein intake may improve measures of renal
function (urine alb...
Adverse effects of ACEI and ARB
• Cough : 0-39%, F>M, class effect
• Angioedema: 0.1-0.2 %: 1hr to <1 wk
• Metallic taste:...
Treatment of DM nephropathy:
Effect of statins
from T. Hostetter
Renal preglomerular vasodilation
Systemic hypertension
Gl...
• Normalize BP. Target <130/80.
• Treat with ACE inhibitors or ARBs.
• Treat hyperlipidemia and hyperglycemia aggressively...
Diabetic Nephropathy: Introduction (2)
Do you know…
• At diagnosis 30% of people with T2DM
have nephropathy
Tobe SW et al....
Category 24-h Timed Spot
collection collection collection
mg/24 h µg/min µg/mg creat
Normal <30 <20 <30
Microalbuminuria 3...
Obese, sedentary, “wrong diet”, genetic predisposition,…….
IGT
DM
Incipient Nephropathy
Overt or Clinical Nephropathy
ESRD...
• Glycemic Control means
– FPG= 90-130 mg/dl
– PPPG <180 mg/dl
– HbA1c <7.0%
– Self-monitoring of blood glucose (SMBG)
– M...
Diabetic nephropathy management
Diabetic nephropathy management
Diabetic nephropathy management
Diabetic nephropathy management
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Diabetic nephropathy management
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Diabetic nephropathy management
Diabetic nephropathy management
Diabetic nephropathy management
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Diabetic nephropathy management
Diabetic nephropathy management
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Diabetic nephropathy management
Diabetic nephropathy management
Diabetic nephropathy management
Diabetic nephropathy management
Diabetic nephropathy management
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  • There are differences in the cumulative incidence rates for the development of end stage renal disease (after patients develop albuminurium) between those who have type I versus type 2 DM. The rate for type 2 DM obviously being quite lower than that for type I. The reasons for these differences are many, but probably include primarily the fact that patients with type 2 DM have a substantial amount of cardiovascular disease and probably die from their cardiovascular disease before they actually develop end stage renal disease, in many cases. Furthermore, a number of patients with type 2 DM have other causes of nephropathy in about 25% of cases, so that there may be other reasons why there may be a slower progression rate. And then finally, patients who have type 2 DM may just have a slower rate of progression of the disease compared to those with type I.There are a number of things that can potentially explain the increase in cardiovascular disease occurring in those patients with diabetes who have increased urinary albumin excretion. Among these is a common genetic predisposition for both of these findings. Endothelial dysfunction certainly occurs in patients with cardiovascular disease, as well as those with increased urinary albumin excretion. Hypertension is a common accompaniment of renal disease in patients with diabetes, and that can certainly make cardiovascular disease worse. Insulin resistance is common to both of these findings. In patients with renal disease, there is an atherogenic dyslipidemia that occurs, and certainly hyperglycemia may contribute to both the development of renal disease as well as cardiac disease.
  • Transcript of "Diabetic nephropathy management"

    1. 1. Diabetic Nephropathy: “You can't cure it so you have to endure it” BY DR.KARTHIK.RAO.N
    2. 2. Current Terminology • Kidney, not Renal (or Reno) • CKD, not CRF • DKD (= diabetic nephropathy) • AKI, not ARF • Still ESRD (End Stage Renal Disease) • Still RRT (Renal Replacement Therapy)
    3. 3. Definition of CKD Structural or functional abnormalities of the kidneys for >3 months, as manifested by either: 1. Kidney damage, with or without decreased GFR, as defined by • pathologic abnormalities • markers of kidney damage, including abnormalities in the composition of the blood or urine or abnormalities in imaging tests 2. GFR <60 ml/min/1.73 m2, with or without kidney damage
    4. 4. Definition and Problem • Progressive in UAE a/w BP and GFR • 35-50% DN in Type 1 after 20 years of disease • 10- ? 20% DN Type 2 in patients on diagnosis ?? • Renal risk is equal in both Type I and II DM • Progressive rise in ESRD: Up to 40% of patients on RRT due to DN • Strong association with cardiovascular risk (20-40 fold higher)
    5. 5. Stages of Chronic Kidney Disease Stage Description GFR (mL/min) 1 Kidney damage normal or GFR ≥90 2 Kidney damage mild GFR 60-89 3 Moderate GFR 30-59 4 Severe GFR 15-29 5 Kidney Failure <15 Use e-GFR and not S Creat in practice
    6. 6. Stages of Diabetic Nephropathy • Hyperfilteration • Stage of Clinical Latency • Incipient Nephropathy • Overt Nephropathy • Renal Failure (Mogensen Staging for T1DM)
    7. 7. Diagnosis Hyperfiltration Clinical Latency Microalbuminuria Macroalbuminuria Renal failure Diabetes Microalbuminuria Dipstick negative Macroalbuminuria Dipstick positive 30 300 mg/d0 New Terminology Micro-albuminuria = High Albuminuria Macroabuminurai = Very high Albuminuria
    8. 8. Stage of hyper- filtration Micro albumi- nuria Macro albumi- nuria Azotemia (Renal failure) End stage Renal disease Normo albumi- nuria NATURAL HISTORY OF NEPHROPATHY IN TYPE 1 DIABETES 15 - 20 yrs 1 yrs4 - 5 yrs
    9. 9. Natural History
    10. 10. Type II Microalbuminuria Macroalbuminuria Renal failure Diagnosis Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Diagnosis Hyperfiltration Clinical Latency Microalbuminuria Macroalbuminuria Renal failure Type 1
    11. 11. Definitions of abnormalities in albumin excretion Because of variability in urinary albumin excretion, two of three specimens collected within a 3- to 6-month period should be abnormal before considering a patient to have crossed one of these diagnostic thresholds. Exercise within 24h, infection, fever, congestive heart failure, marked hyperglycemia, marked hypertension, pyuria, and hematuria may elevate urinary albumin excretion over baseline values. Diabetes care 2004; 27(1): S79-S83
    12. 12. Type II Macroalbuminuria Renal failure Diagnosis Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Diagnosis Hyperfiltration Clinical Latency Microalbuminuria Macroalbuminuria Renal failure Type 1
    13. 13. Type II Renal failure Diagnosis Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Diagnosis Hyperfiltration Clinical Latency Microalbuminuria Macroalbuminuria Renal failure Type 1
    14. 14. Microalbuminuria & Proteinuria Normal Microalbuminuri a Overt proteinuria F M F M Albumin/creatinine ratio (mg/mmol) <3.5 <2.5 >3.5 >2.5 >30 Equivalent Albumen excretion (mg/day) <30 30-300 300 •Diagnosis of microalbuminuria based on 2 out of 3 urine samples in absence of UTI •After 5 years of Dx in T1DM & than annually. •At the time of diagnosis in T2DM.
    15. 15. U/A at Diagnosis (Type 2 patients) Random spot collection Albumin:creatinine Repeat 3x in 3-6 months 2 of 3 ≥ 30mg/g creatinine Microalbuminuria, begin treatment Nephropathy Quantify µalb:Cr Consider referral No microalbuminuria Re-screen yearly Negative Positive No Yes
    16. 16. 16 What are Diabetics with Nephropathy Dying From? Stroke Myocardial Infarction Heart Failure Sudden Death
    17. 17. Risk Factors : Non Modifiable • Race: Indo-Asians, Africans, Hispanics, Native Americans. • Familial clustering: In Type 1 DM if 1* relative > 80% chances of developing DN. In Type 2 DM (Pima Indians) 14%, 23% and 46% (0,1,2 parents DM) • Genetic influence ACE gene polymorphism (DD in Type 2) Ag-II type 2 receptor gene (AT2) on X-chromosome. (AA haplotype risk than GT haplotype in type 1 DM) Inheritance of one allele of the aldose reductase gene, • Low Birth weight • Age Type 1 onset < 5 risk of ESRD but risk in T2DM in Pima indians <20 yrs. Type 1 no proteinuria till age 25 risk <1 % • Elevated pro-renin levels.
    18. 18. Risk factors: Modifiable • Hypertension • Dyslipidemia • Smoking • Poor glycemic control • Obesity • Oral Contraceptives • Increased protein intake
    19. 19. Natural History in Type 2 DM • GFR decline once proteinuria present 12 ml/min/year untreated • Patients often die of other causes (CVS disease) before ESRF • CVS risk rises 2-3X with microalbuminuria, 9-10X with clinical proteinuria • Higher rates of ESRF in T1DM
    20. 20. Hypertension • Greater than 140/90 increases the risk of diabetes • 50-60% of newly diagnosed patients also have HTN at diagnosis • An interesting note: A family history of HTN in a child with Type 1 diabetes their risk of developing nephropathy
    21. 21. Undesirable lipid levels • HDL less than 35 mg/dL • Triglycerides greater than 150 mg/dL • Think diabetes or hypothyroidism with the above lipid profile • Draw a FBS and a TSH
    22. 22. Predictors of progression • In normoalbuminuric person • Glycemic control • In established DN • Hypertension • Degree of proteinuria • In renal biopsy • Mesangial expansion • Tubulointerstitial lesions
    23. 23. • Hyperglycaemia Early histological lesions reversible with normoglycaemia • Hypertension Predicts microalbimunuria, proteinuria paralleled by gradual rise in BP Correlation between BP and rate of of GFR • Proteinuria Induces tubulointerstitial damage/ contributes to progression Highly selective in early disease Pathogenesis of DN
    24. 24. Oparil et al. Ann Intern Med 139:761-76, 2003. ANG II ANG II
    25. 25. Cross-talk between the Insulin and Aangiotensin- II Angiotensin II insulin sensitivity & insulin secretion, explaining the antidiabetogenic effect of RAS blockade Hyperinsulinemia enhances Ang II- induced transcriptional activity in vascular smooth muscle cells
    26. 26. Treatment 1. Glycemic control 2. Blood pressure control 3. Angiotensin 2 control 4. Proteinuria control 5. Cholesterol control
    27. 27. DCCT 1400 T1DM Intensive Conventional HbA1C 7.3% 9.1% Reduction in Retinopathy- 47% Microalbumnuria- 39% Clinical Nephropathy- 54% Neuropathy- 60% Benefits of intensive control persisted even after study concluded and glycemic control worsened. After 17 years 50% reduction in macrovascular complications.
    28. 28. Strict glycemic control prevents microalbuminuria in patients with type 1: 2.2%/year DN in Intensive and 3.4% in conventional
    29. 29. Randomized prospective trial of treatment strategies in type II diabetes ukpdsType 2 diabetic patients 5,102 Person years follow-up 53,000 Intensive Conventional HbA1c 7% 7.9% At 12 years 23 % 34 % Each 1% decrease in HbA1C decreases microvascular complications by 35%. Macrovascular advantage is seen after 10 years. Strict BP control decreased microvascular complications.
    30. 30. Benefits of Glycemic Control •Delay the development of albumin excretion •Stabilize or protein excretion in pts with UAE •Slow the progressive renal injury in Macroalb. •May reverse early structural changes UKPDS Study : Glycemic control is less than the benefit from blood pressure control
    31. 31. ACEi are good ARB are good What about both together?
    32. 32. 33 Ang I Ang II Progressive Diabetic Nephropathy ACE Renal Injury and Proteinuria ACEi AT1 Receptor Non-ACE Pathways Aldosterone MRA ARB Can Dual Blockade of the RAAS Improve Renal Outcomes in Diabetic Nephropathy? + +
    33. 33. CALM Study • N= 200 • Type II DM with microalbuminuria • Randomized to: • Lisinopril 20 mg qd • Candesartan 16 mg qd • Combination of lisinopril 20 mg and candesartan 16 mg Mogensen CE, Et al. BMJ 2000; 321: 1440-4. Candesartan and Lisinopril Microalbuminuria (CALM) 24 39 50 0 10 20 30 40 50 ReductioninAlbuminuria(%) Candesartan Lisinopril Combination
    34. 34. Calcium channel blockers • Verapamil does not delay development of microalbuminuria • Verapamil does reduce proteinuria in diabetics independent of changes in BP. Side effect: FGGS & TIF. Aldosterone antagonists • Spironolactone reduces proteinuria in diabetics • Change in proteinuria is independent of blood pressure • All patients were treated with an ACEi or ARB • 24-Hr ambulatory BP fell 6/2 Schjoedt KJ, Et al. Kidney International 2006; 70: 536-542.
    35. 35. ARBs: Evolution of protective benefits ↓BP ↓Stroke ↑Glycemic control ↓Heart failure ↓Renal dysfunction ↓CHD (?)
    36. 36. ONTARGET • Telmisartan (16.7%) noninferior; combination (16.3%) not superior to ramipril (16.5%) for primary endpoint (CV death, MI, stroke, heart failure) • Greater incidence of hypotension in combination (4.8%) and telmisartan (2.7%) groups, compared with ramipril group (1.7%) (p < 0.001) Trial design: Patients at high risk for cardiovascular events, but without heart failure, were randomized to telmisartan, ramipril, or the combination. Patients were followed for a median of 56 months. Results Conclusions The ONTARGET investigators. N Engl J Med 2008;358:1547-59 Telmisartan (n = 8,542) Combination (n = 8,502) • Either telmisartan or ramipril, but not both, can be used in hypertensive patients at high risk for cardiovascular events • Side effects greater with combination therapy 16.7 16.3 % 0 10 Primary endpoint 20 Ramipril (n = 8,576) 16.5 0 10 15 5 Mortality 11.6 12.5 11.8 % (p < 0.004*) (p = ns) * Telmisartan vs. ramipril for noninferiority
    37. 37. RENIN INHITORS PLUS ARBS/ACEI
    38. 38. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): • To determine whether aliskiren 300 mg once daily, reduces CV and renal morbidity and mortality compared with placebo when added to conventional treatment (including ACEi or ARB) • Included high-risk type 2 diabetes patients
    39. 39. Treatment  Blood pressure control  Glycemic control 3. Proteinuria control 4. Cholesterol control
    40. 40. Protein restriction slows progression of DN
    41. 41. Is Anemia Causing Cardiovascular And Renal Disease In Diabetics, Or is it Just A Marker?
    42. 42. Hypothesis: Anemia is an Important CV Risk Factor in Chronic Kidney Disease Chronic Kidney Disease Cardiovascular disease Anemia ©2005. American College of Physicians. All Rights Reserved.
    43. 43. < 2 % pts of DRD require RRT because others often die of CVD before reaching ESRD. Dialysis Get an early vascular access for HD Offer PD to patients with adequate manual dexterity I P Insulin therapy in PD pts Offer HD to diabetic with severe vascular disease Transplantation Renal and renal-pancreas transplantation Preemptive transplantation (GFR<30 mL/min) Evaluation for CAD Post-Tx UTI, Allograft Rejection, Glycemic Control Management of ESRD in DN
    44. 44. How Should We Manage Patient With Diabetic Nephropathy Today? Parameter • Lower BP…………… • Block RAAS…… • Improve glycemia …. • Lower LDL cholesterol.. • Anemia management ... • Endothelial protection… • Smoking…………… Target < 130/80 mmHg ACEi or ARB to max HbA1c < 6.5% (Insulin) < 100 (70) mg/ statin + other Hb 11-12 g/dl (Epo + iron) Aspirin daily Cessation
    45. 45. Conclusions • Diabetic nephropathy is the most common cause of ESRD in the world • ESRD is a rare out- come among diabetics • Just over half of diabetics will develop nephropathy • Blood pressure control • Glycemic control • Angiotensin 2 reduction • Proteinuria reduction • ACEi + ARB • Statins • Aldosterone antagonists • Dihydropyridine calcium channel blockers
    46. 46. Key messages • Screening for diabetic renal disease is easy and should be performed annually • Good glycaemic control is the main Pry prevention therapy • Once microalbuminuria confirmed RAS blockade is must • BP targets should be individualised • Treatment aims to stabilise e-GFR & maintain/ UAER • Attention to all vascular risk factors is vital • If RRT becomes necessary this needs to be carefully planned well in advance
    47. 47. Diabetic Nephropathy 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) 43% 23% 12% 3% 19% Diabetes Hypertension Glomerulonephritis Cystic Kidney Other Causes
    48. 48. Five Stages of Kidney Disease 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.
    49. 49. Investigations Urinary Protein assessment Dipstick 24hour urinary protein estimation Albumin: Creatinine ratio > 2.5 in males and > 3.5 in females is abnormal Confirm with Albumin excretion rate (AER) of 20- 200ug/min or 30-300mg/24hrs. This requires timed urine collection
    50. 50. Five Stages of Kidney Disease (con’t.) 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.
    51. 51. Screening for Diabetic Nephropathy Test When Normal Range Blood Pressure1 Each office visit <130/80 mm/Hg Urinary Albumin1 Type 2: Annually beginning at diagnosis Type 1: Annually, 5-years post-diagnosis <30 mg/day <20 g/min <30 g/mgcreatinine 1American Diabetes Association: Nephropathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S79-S83, 2004
    52. 52. Treatment of Diabetic Nephropathy • 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
    53. 53. • Glycemic Control – Preprandial plasma glucose 90-130 mg/dl – A1C <7.0% – Peak postprandial plasma glucose <180 mg/dl – Self-monitoring of blood glucose (SMBG) – Medical Nutrition Therapy • Restrict dietary protein to RDA of 0.8 g/kg body weight per day Treatment of Diabetic Nephropathy (cont.)
    54. 54. Treatment of End-Stage Renal Disease (ESRD) There are three primary treatment options for individuals who experience ESRD: 1. Hemodialysis 2. Peritoneal Dialysis 3. Kidney Transplantation
    55. 55. Hemodialysis • 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
    56. 56. • 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 Hemodialysis (cont.)
    57. 57. Peritoneal Dialysis • 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
    58. 58. Peritoneal Dialysis (cont.) • Peritoneal Dialysis Diet – Limit salt and fluid intake – Consume more protein – Some potassium restrictions – Reduce caloric intake • Complications – Peritonitis
    59. 59. Kidney Transplant • 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
    60. 60. How Can You Prevent Diabetic Kidney Disease? • Maintain blood pressure <130/80 mm/Hg • Maintain preprandial plasma glucose 90- 130 mg/dl • Maintain postprandial plasma glucose <180 mg/dl • Maintain A1C <7.0%
    61. 61. 63 Albuminuria then Proteinuria • Microalbuminuria first (lower MW) – Raised by GFR (i.e. BSL, protein diet, fever, exercise) • Spot urine ACR or PCR – more convenient than 24hr collection – more accurate than urinalysis – adjusts for fluid intake – underestimates the muscular patient
    62. 62. 64 Diabetic Nephropathy • From haemodynamic & metabolic stresses • Metabolic stress – deposition of advanced glycosylation end products in connective tissue & sml vessels. • May take 10-20 yrs but many T2DM asymptomatic for several yrs, hence nephropathy may already be present at Dx
    63. 63. 65 Nephropathy Risk Factors • DM Type & Duration – 20% of Type I after 20 years – 40% of Type II any duration • Poor diabetic control • Hypertension • Aboriginal > Indian > Caucasian • Smokers • Family history
    64. 64. 66 • 1st clinical sign is microalbuminuria (ACR) • Kidney not able to catabolise albumin • This can also occur transiently with – Fever – Exercise – Short term hyperglycaemia – High protein meal • Hence, repeat at a later date/rule out reversible • DM + HPT,  x 20 risk of progressive nephropathy • DM + HPT + poor diabetic & lipid control,  x 40 risk
    65. 65. 67 Nephropathy Risk Factors • DM Type & Duration – 20% of Type I after 20 years – 40% of Type II any duration • Poor diabetic control • Hypertension • Aboriginal > Indian > Caucasian • Smokers • Family history
    66. 66. 68 Nephropathy Risk Factors • Modifiable – HbA1c, BP & total cholesterol (Odds Ratio 43) – Obesity, smoking • Non-modifiable – Age, ethnicity, male sex
    67. 67. 69 Delaying Complications • Tight diabetic control – Prevention of microvascular Cmplx • Risk of hypos • Tight BP control – Prevention and management of micro & macro Cmplx – Use ACEI, ARB’s or both combined
    68. 68. 70 ACE Inhibitors can prevent progression of renal failure 120 160 200 240 280 320 350 400 80 0 1 2 3 4 5 6 Years Ann Intern Med 118 577-581.1993 Placebo Enalapril 85 90 95 100 105 110 80 0 1 2 3 4 5 6 Years Placebo Enalapril Normotensive Type 2 Diabetics Proteinuria (mg/day) % Initial GFR
    69. 69. 71 ACEI/ARB Proteinuria Remission H L H L 30 40 50 60 70 80 90 2000 Jan 2000 2001 2002 Creatinine - Plasma umol/L H 0 500 1000 2000 Jan 2000 2001 2002 Protein/Creat Ratio - Urine mg/mmol
    70. 70. 72 Q. Which features are typical of diabetic CKD at presentation ? • Haematuria NO • Small scarred kidneys NO • Progress to ESKD in <2yrs NO • Associated retinopathy YES • -blockers better than ACE-I Rx NO
    71. 71. 73 Diabetes and ESKD • Reducing insulin requirements • Difficult vascular access • Accelerated macrovascular disease • Advanced microvascular disease • Frequent sepsis • Silent ischaemia • 2-3 x death rate vs non-DM patients
    72. 72. 74 How can DM effect Dialysis? • Autonomic neuropathy – may suffer hypotension increased by large fluid shift in HD • Uncontrolled blood sugars – may absorb some glucose in PD fluid • Severe PVD – difficult to get vascular access for HD • PVD may also affect peritoneum and reduce PD success • Increased risk of infections – problem in both • Transplants – new kidneys develop nephropathy, hence good glycaemic control important
    73. 73. 75 Strict BSL Control in early Type I • Target HbA1c < 7% • For every 1% HbA1c: – 10% CVD – 40% Microvascular Cmplx • BUT: • Doubles risk of hypoglycaemia • Loss of control with DM duration: – 50% at 3yr – 30% at 6yr – 15-25% at 9yr (= % patients with HbA1c < 7% on Met or OHA alone)
    74. 74. 76 Strict BSL Control in DM CKD • AND: • Minimal benefit if overt proteinuria • Diabetes “cured” by advancing CKD – reduced appetite and CHO intake – prolonged insulin half-life – false elevation of HbA1c by 0.5-1%
    75. 75. 77 Metformin in CKD • No hypos or weight gain • Inexpensive • BUT: – Renally-excreted – Excess doses anorexia, diarrhoea – Dose adjust to GFR: 2g to 250mg/day – Protocol says • eGFR 30 – 59 max 1gm/day • cease when eGFR <30 but… – Risk of fatal lactic acidosis if unwell
    76. 76. 78 Glitazones in DM • Av.1% fall in HbA1c as monoRx or add-on • Preserves beta-cell fn - use early • Durable effect >3yrs • BUT: – 1-2/12 delayed onset – Average 4kg SC fat gain, visceral fat loss – Oedema (Na+/H20, vasc. permeability) – Expensive
    77. 77. 79 Strict BP Control at any stage • ½’s (or even stops) rate of fall in GFR • Greater benefit than tight BSL control • Falling BP Target = 120/70 currently • Preferential use of ACEi/ARBs • Complete regression of proteinuria possible • Helps all micro- & macrovascular disease • (Parving, UKPDS, Captopril Trial, MicroHOPE, IRMA/IDNT, JNC VI)
    78. 78. 80 Use of ACEi/ARBs: actions • Antihypertensive – by salt excess, by thiazides – need mean of 3 agents in mild CKD • Antiproteinuric – 30-50% alone, 40-70% together • Renoprotective – corrects GFR, expected 30% creatinine
    79. 79. Creatinine- it’s the best we have!
    80. 80. Rough GFR  Equations should be used only in the steady state  Not useful in ARF  Reasonable criteria ◦ CrCl> 50ml/min ◦ CrCl 10 – 50 ml/min ◦ Crcl< 10 ml/min ◦ Oliguric and non oliguric Creatinine GFR 1 100 2 50 3 25 4 12.5 5 6.125 6 3.06125
    81. 81. Natural history of DN
    82. 82. Diabetes 1,2 3 4 5 Time GFR Creat
    83. 83. Problems  Precautions  Blood pressure control  Dietary protein restriction  Management of MBD  Management of anemia  Vaccination  Volume control  Cardiovascular disease screening  Options of renal replacement
    84. 84. Precautions  No nephrotoxics ◦ Impair glomerular function: NSAIDS ◦ Impair tubular function: Aminoglycosides ◦ NO contrast agent exposure  Drug dose adjustment  Treat intercurrent infections properly  Educate about native drugs  Early referral to nephrologist
    85. 85. Blood pressure management Systemic BP reduction Intra-glomerular BP reduction Anti-proteinuric effect Blood pressure control Beta blockers Alpha -blockers Vasodilators ARB ACEi Preservation of other target organs Preservation of kidneys
    86. 86. Protein restriction  Preservation of organ repair  Daily dietary requirement (FAO) ◦ 0.6 g/Kg/d plus 2 SD= 0.8 g/Kg/d  MDRD study ◦ Dietary protein restriction may offer a benefit  Remember to preserve adequate calories
    87. 87. Secondary hyperparathyroidism 89
    88. 88. 90 Decreased GFR Hyperphosphatemia Hypocalcemia Low vitamin D + decreased activation + Resistance Secondary hyperparathyroidism Binders Phosphate binder +/- Calcium supplement Vitamin D/ analogues Calcimimetics
    89. 89. 91 Decreased GFR Hyperphosphatemia Hypocalcemia Low vitamin D + decreased activation + Resistance Secondary hyperparathyroidism Binders Phosphate binder +/- Calcium supplement Vitamin D/ analogues Calcimimetics
    90. 90. Diabetic Nephropathy  DN occurs in 35-40% of patients with type I diabetes (IDDM) whereas it occurs only in 15-20% of patients with type II diabetes (NIDDM).  Definition or Criteria for diagnosis of DN  Presence of persistent proteinuria in sterile urine of diabetic patients with concomitant diabetic retinopathy and hypertension.
    91. 91. BMD  Dietary phosphate restriction  Phosphate binders ◦ Aluminium ◦ Calcium ◦ Magnesium ◦ Non aluminium, calcium, magensium binders  Replenishment of vitamin D stores  Activated vitamin D 1, 25 (OH)2D3  Vitamin D analogues ◦ Paricalcitrol ◦ Doxercalcitriol
    92. 92. Anemia management EPO deficiency Defect in iron absorption B12 and folate deficiency Diseases like myeloma Hyperparathyroidism Drugs like ARB Aluminum toxicity Blood loss Hemolysis Pure Red Cell Aplasia
    93. 93. Correction of anemia  Identify iron deficiency  Oral iron vs parenteral iron  Iron sucrose  Don’t overload iron  Avoid transfusions  EPO therapy if iron replete  Target 11 to 12 g/dl  Start at small dose and titrate upwards  Twice weekly to thrice weekly  Newer analogues may be used less frequently
    94. 94. Vaccinations  Hepatitis B ◦ 20 mcg each deltoid IM 0, 1, 2, 6 months ◦ Check Anti HBS titre post vaccination after 3rd dose ◦ Only 60 % seroconvert in ESRD  Pneumococcal vaccine  Influenza vaccine
    95. 95. Volume control  Problems with salt and water excretion in CKD is relatively later  Proteinuric conditions may develop this problem early  Diabetic remain proteinuric even while fibrosis continues to proceed  Fluid restriction and salt restriction is important
    96. 96. Diabetes  Asymptomatic bacteriuria is more common (20%)  UTIs are likely to be more severe in diabetic than nondiabetic women  Asymptomatic bacteriuria often precedes symptomatic UTI in type 2 diabetes [RR] 1.65  Risk factors for UTI in diabetics includes those  who take insulin (relative risk 3.7)  longer diabetes duration (>10 years, relative risk 2.6) ○ but not glucose control  Emphysematous pyelonephritis, xanthogranulomatous UTI and fungal UTI are
    97. 97. Diabetic Nephropathy A clinical syndrome DM + Persistent albuminuria, Worsening proteinuria, Hypertension & progressive renal failure
    98. 98. Diabetic nephropathy (DN) is a major cause of ESRD, and the incidence of diabetes mellitus is rising rapidly.
    99. 99. Diabetic Nephropathy  DN occurs in 35-40% of patients with type I diabetes (IDDM) whereas it occurs only in 15- 20% of patients with type II diabetes (NIDDM).  Definition or Criteria for diagnosis of DN  Presence of persistent proteinuria in sterile urine of diabetic patients with concomitant diabetic retinopathy and hypertension.
    100. 100. Effect of Angiotensin Blockade Afferent arteriole Efferent arteriole Glomerular pressure ( GFR) Glomerulus Bowman’s Capsule Angiotensin II Proteinuria A II blockade:
    101. 101. Irbesartan in patients with type 2 diabetes & microalbuminuria study  590 NIDDM patients with HTN and microalbuminuria with nearly normal GFR.  Randomly assigned to placebo, 150 mg or 300 mg of irbesartan for 2 years.  Primary outcome was time to the onset of diabetic nephropathy (urinary albumin excretion rate >200 mcg/min and at least 30% greater albuminuria)  14.9% patients on placebo group, 9.7% of irbesartan 150mg group and 5.2% of irbesartan 300 mg group reached the primary point.  (Parving et al, NEJM, 2001)
    102. 102. ARBs in NIDDM,HTN & microalbuminuria-Parving 2001
    103. 103. D.N.-Management  ACEI or AII RB- in both expt & human Reduce glomerular hypertension Reduce proteinuria independent of hemodynamic effects Reduce glomerular hypertrophy well tolerated apart from hyperkalemia & worsening of anemia in severe CRF Cautious use in presence of severe renovascular disease
    104. 104. DN: ADA Position Statement Screening: Perform an annual test for the presence of microalbuminuria in 1) type 1 diabetic patients who have had diabetes > 5 years and 2) all type 2 diabetics patients starting at diagnosis. Treatment: • In the treatment of albuminuria/nephropathy both ACE inhibitors and ARBs can be used: • In hypertensive and nonhypertensive type 1 diabetic patients with microalbuminuria or clinical albuminuria, ACE inhibitors are the initial agents of choice • In hypertensive type 2 diabetic patients with microalbuminuria or clinical albuminuria, ARBs are the initial agents of choice. • If one class is not tolerated, the other should be substituted American Diabetes Association: Position Statement Diabetes Care 25:S85-S89, 2002
    105. 105. UK Prospective Diabetes Study (UKPDS) Major Results: Powerful Risk Reductions Better blood pressure control reduces…  Strokes by > one third  Serious deterioration of vision by > one third  Death related to diabetes by one third Better glucose control reduces…  Early kidney damage by one third  Major diabetic eye disease by one fourth Turner RC, et al. BMJ. 1998;317:703- 713.
    106. 106. National Kidney Foundation Recommendations on Treatment of HTN and Diabetes  Blood pressure goal: 130/80 mmHg  Target blood pressure: 125/75 for patients with >1 gram/day proteinuria  Blood pressure lowering medications should reduce both blood pressure + proteinuria  Therapies that reduce both blood pressure and proteinuria have been known to reduce renal disease progression and incidence of ischemic heart disease Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.
    107. 107. Treatment Objectives to Prevent Macrovascular Disease in Diabetic Patients  Hypertension ◦ BP < 130/80 mmHg  Hypercholesterolemia ◦ LDL < 100 mg/dL  Hyperglycemia ◦ Hgb A1C < 7.0 % American Diabetes Association Clinical Practice Recommendations. Diabetes Care. 2001;24(suppl1):S1- S133.
    108. 108. Management of HTN and Chronic Renal Disease (CRD) in Diabetics  Reduce BP to <130/80 mmHg  Use multiple antihypertensive drugs (ACEI, ARB, diuretic, CCB, beta-blocker)  Maximal reduction of proteinuria  Treat hyperlipidemia (LDL <100 mg/dL)  Control Hgb A1C to <7%  Low salt diet (<2 gm NaCl/day)  Stop cigarette smoking
    109. 109. Diabetic Nephropathy Clinical syndrome characterised by persistent albuminuria (>300mg/24hrs) on at least 2 occasions separated by 3 months.
    110. 110. Epidemiology Incidence of Diabetic Nephropathy in Type 1 Diabetes 4-17% 20 years 16-30% 30 years 30-40% 40 years
    111. 111. Epidemiology Incidence of Diabetic Nephropathy in Type 2 Diabetes 5% at diagnosis 20% after 20 years
    112. 112. Screening for Microalbuminuria Albumin excretion increased due to  Strenuous exercise  Oral Protein intake  Urinary infection  Fluid loading  Pregnancy
    113. 113. Urinary Albumin Excretion Rates Normoalbuminuria < 30mg/day Microalbuminuria 30-300mg/day Overt Nephropathy > 300mg/day
    114. 114. Screening for Microalbuminuria Type 1: Yearly after 5 years of diagnosis Type 2: Annually from diagnosis
    115. 115. Protein Kinase C Renal injury due to hyperglycaemia increase reactive oxygen species. Activation of PK C and TGF b results in increased: Vascular Contractility Blood Flow Cellular Proliferation Vascular Permeability
    116. 116. Inhibition of PKC by Ruboxistaurin in Rats  Reduces Glomerular Hyperfiltration  Albuminuria  Extra cellular Matrix accumulation
    117. 117. Mechanisms for the Renoprotective Effect of ACE Inhibitors  Lower Systemic Blood Pressure  Lower Intra glomerular Pressure and filtration rates  Reduce Proteinuria
    118. 118. Mechanisms for the Renoprotective Effect of ACE Inhibitors Inhibit non Heamodynamic effects of Angiotensin on various cell types  Reduction in Cytokine and Growth factor synthesis e.g. TGF β  Mesangium: Reduced Cell proliferation Hypertrophy Matrix Expansion
    119. 119. Mechanisms for the Renoprotective Effect of ACE Inhibitors Reduction in Oxidative Stress Inhibit macrophage activation, proliferation and migration
    120. 120. Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Glomerular sclerosis Hyperglycemia Genetic factors metabolism of glom. cells Treatment of DM nephropathy: Glucose control from T. Hostetter
    121. 121. Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Glomerular sclerosis Hyperglycemia Genetic factors metabolism of glom. cells Treatment of DM nephropathy: Hypertension control from T. Hostetter
    122. 122. Blood pressure management Systemic BP reduction Intra-glomerular BP reduction Anti-proteinuric effect Blood pressure control Beta blockers Alpha -blockers Vasodilators ARB ACEi Preservation of other target organs Preservation of kidneys
    123. 123. Treatment • Hypertension control: – Lower the BP, slower the decline in GFR in patients with diabetic nephropathy – JNC VI recommended BP < 130/85 mmHg in patients with renal insufficiency – Patients with CKD and > 1g proteinuria, BP goal should be < 125- 130/75-80 mmHg
    124. 124. Role of Aldosterone in the Pathogenesis of Diabetic Nephropathy
    125. 125. Treatment • ACE inhibitors: – Type I diabetes with nephropathy: captopril vs. placebo – 50% RR of combined end points of death, dialysis and transplantation in ACEI group independent of BP Lewis et al. NEJM, 1993
    126. 126. Treatment • Angiotensin-receptor blockers: – RENAAL study(2001) • 1513 pts with type II DM and nephropathy. Losartan vs. placebo. Losartan reduced the rate of doubling of cr by 16% but no effect on the rate of death. – IDNT(2001) • 1715 type II DM pts with nephropathy. Irbesartan vs. amlodipine vs. placebo. Irbesartan has 20% lower risk of reaching endpoints compared to placebo and 23% lower incidence than that in the amlodipine group
    127. 127. Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Glomerular sclerosis Hyperglycemia Genetic factors metabolism of glom. cells Treatment of DM nephropathy: Effect of ACEIs and ARBs from T. Hostetter
    128. 128. Diabetic Nephropathy: Important Message • Lower blood pressure < 130 / 80 mmHg • Reducing Proteinuria • Inhibition of Renin-Angiotensin System • Multiple risk factor intervention – Glycemia – Dyslipidemia – Physical activity – Aspirin – Smoking cessation
    129. 129. ACEi- or ARB-Based Regimens for Diabetic Nephropathy Do Not Go Far Enough!
    130. 130. Diabetic Nephropathy: Important Message • Small short-term studies suggest combinations of ACEi and ARB reduce proteinuria synergistically – Greater reductions in proteinuria with or without additional lowering in blood pressure – Hyperkalemia and Increased creatinine not well documented • Safety and Efficacy of combination ACEi and ARB in diabetic with nephropathy not well established
    131. 131. Secondary hyperparathyroidism Abnormalities in metabolism of calcium and phosphorus in patients with chronic kidney disease
    132. 132. Targets Stage Calcium* Phosphorous PTH Stage 3 8.4 to 9.5 2.7 to 4.6 35-70 Stage 4 8.4 to 9.5 2.7 to 4.6 70-110 Stage 5 8.4 to 9.5 3.5 to 5.5 150 to 300 *Corrected calcium
    133. 133. BMD • Replenishment of vitamin D stores • Activated vitamin D 1, 25 (OH)2D3 • Vitamin D analogues – Paricalcitrol – Doxercalcitriol • Dietary phosphate restriction • Phosphate binders – Aluminium – Calcium – Magnesium – Non aluminium, calcium, magensium binders
    134. 134. Anaemia • May occur when GFR < 50 % & almost always present when GFR < 30 % • Correct deficiencies – Iron, Folic acid, Vit B12, Pyridoxine • Erythropoietin 75 - 150 iu/kg SC – With Iron supplements – Expensive therapy Rs. 8 - 10, 000 / month – Hb % maintained at 11 - 12 • > 13 in pts with CAD
    135. 135. Vaccinations • Hepatitis B – 20 mcg each deltoid IM 0, 1, 2, 6 months – Check Anti HBS titre post vaccination after 3rd dose – Only 60 % seroconvert in ESRD • Pneumococcal vaccine • Influenza vaccine
    136. 136. Fluid management Many diabetics have nephrotic state and severe edema and need rigorous salt & fluid restriction • Severe edema - 600 - 800 ml / day • Mild to moderate - equal to UOP • No edema - UOP + insensible losses
    137. 137. Cardiovascular disease screen • Renal disease is a cardiovascular risk factor • CKD promotes vascular calcification • Non invasive evaluation important • Contrast agents carries risk of RCIN- benefits to risk
    138. 138. Options of renal replacement • Hemodialysis • Peritoneal dialysis • Renal transplantation
    139. 139. Peritoneal dialysis Advantages • Slow, gentle • Round the clock clearance • Greater salt, fluid and dietary freedom • Mobility • No need for vascular access Disadvantages • Visual acuity important • Metabolic problems and some mechanical problems • Peritonitis
    140. 140. Others • Lipid lowering - diet, statins • Low dose aspirin • Avoid nephrotoxic drugs & contrast procedures • Prevent & treat infections energetically • Hepatitis B immunization – Early immunization ideal – if Cr. > 3 double & more frequent dosing
    141. 141. Diabetic Nephropathy: Some Novel Therapies Under Investigation • Pirfenidone –antifibrotic agent • Aliskerin anti-renin agent • Robuxistaurin- Protein Kinase C Beta-1 antagonist • Advanced Glycation Endproduct antagonists
    142. 142. Recommendations: Nephropathy treatment (1) • Nonpregnant patient with micro- or macroalbuminuria – Either ACE inhibitors or ARBs should be used (A) ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S33.
    143. 143. Control blood sugars: which drug to use ? • Drugs contraindicated: Metformin • Preferably not used: Glibenclamide, Chlorpropamide • Can be used: Glimiperide, Repaglinide, Pioglitazone • Insulin: prefer Target : HbA1c <7 %, FPG: <100 mg/dl, PPBG<140 mg/dl
    144. 144. Blood pressure management  Preferred drugs: Angiotensin receptor blocker ACE inhibitor Non DHP calcium channel blocker: Diltiazem Diuretic Beta blocker Target blood pressure : 125/75 mm Hg
    145. 145. Recommendations: Nephropathy treatment (2) • In patients with type 1 diabetes, hypertension, and any degree of albuminuria – ACE inhibitors have been shown to delay progression of nephropathy (A) • In patients with type 2 diabetes, hypertension, and microalbuminuria – Both ACE inhibitors and ARBs have been shown to delay progression to macroalbuminuria (A) ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S33.
    146. 146. Recommendations: Nephropathy Treatment (4) • Reduction of protein intake may improve measures of renal function (urine albumin excretion rate, GFR) (B) – To 0.8 –1.0 g x kg body wt–1 x day–1 in those with diabetes, earlier stages of CKD – To 0.8 g x kg body wt–1 x day–1 in later stages of CKD • When ACE inhibitors, ARBs, or diuretics are used, monitor serum creatinine, potassium levels for development of acute kidney disease, hyperkalemia (E)
    147. 147. Adverse effects of ACEI and ARB • Cough : 0-39%, F>M, class effect • Angioedema: 0.1-0.2 %: 1hr to <1 wk • Metallic taste: captopril • Hyperkalemia • Worsening renal failure
    148. 148. Treatment of DM nephropathy: Effect of statins from T. Hostetter Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Glomerular sclerosis Hyperglycemia ROS Genetic factors metabolism of glom. cells
    149. 149. • Normalize BP. Target <130/80. • Treat with ACE inhibitors or ARBs. • Treat hyperlipidemia and hyperglycemia aggressively. • Moderate protein restriction (0.8- 1.0 gm/kg/day). • Treat cardiovascular disease aggressively. • Refer to nephrologist early in course of azotemia. Management of Diabetic Nephropathy-Rx
    150. 150. Diabetic Nephropathy: Introduction (2) Do you know… • At diagnosis 30% of people with T2DM have nephropathy Tobe SW et al. CMAJ; 2002; 167 (5):499-503
    151. 151. Category 24-h Timed Spot collection collection collection mg/24 h µg/min µg/mg creat Normal <30 <20 <30 Microalbuminuria 30-300 20-199 30-299 Overt Nephropathy >300 ≥200 ≥ 300 (Macroalbuminuria) (Alb./Cr.ratio) Definitions of abnormality in albumin excretion Diabetic Nephropathy : Introduction (3)
    152. 152. Obese, sedentary, “wrong diet”, genetic predisposition,……. IGT DM Incipient Nephropathy Overt or Clinical Nephropathy ESRD Progression of Nephropathy (2)
    153. 153. • Glycemic Control means – FPG= 90-130 mg/dl – PPPG <180 mg/dl – HbA1c <7.0% – Self-monitoring of blood glucose (SMBG) – Medical Nutrition Therapy • Restrict dietary protein to RDA of 0.8 g/kg body weight / day • BP control – Maintain BP <130/80 mm/Hg Glycemic control is a must….
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