Diabetic Nephropathy Treatment and Management

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 ESRD (End Stage Renal Disease)
• Still RRT (Renal Replacement Therapy)

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

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)

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

Stages of Diabetic Nephropathy
• Hyperfilteration
• Stage of Clinical Latency
• Incipient Nephropathy
• Overt Nephropathy
• Renal Failure
(Mogensen Staging for T1DM)

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

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

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

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

Type II
Macroalbuminuria
Renal failure
Diagnosis
Diagnosis
Hyperfiltration
Clinical Latency
Microalbuminuria
Macroalbuminuria
Renal failure
Type 1

Type II
Renal failure
Diagnosis
Diagnosis
Hyperfiltration
Clinical Latency
Microalbuminuria
Macroalbuminuria
Renal failure
Type 1

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.

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
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 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.

Risk factors: Modifiable
• Hypertension
• Dyslipidemia
• Smoking
• Poor glycemic control
• Obesity
• Oral Contraceptives
• Increased protein intake

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

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

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

Predictors of progression
• In normoalbuminuric person
• Glycemic control
• In established DN
• Hypertension
• Degree of proteinuria
• In renal biopsy
• Mesangial expansion
• Tubulointerstitial lesions

• 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

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 antidiabetogenic
effect of RAS blockade
Hyperinsulinemia
enhances Ang II-
induced transcriptional
activity in vascular
smooth muscle cells

Treatment
1. Glycemic control
2. Blood pressure control
3. Angiotensin 2 control
4. Proteinuria control
5. Cholesterol control

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.

Strict glycemic control prevents microalbuminuria in patients with
type 1: 2.2%/year DN in Intensive and 3.4% in conventional

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.

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

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
Aldosterone
MRA
ARB
Can Dual Blockade of the RAAS Improve
Renal Outcomes in Diabetic Nephropathy?
+
+

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

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.

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 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

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

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
Anemia
©2005. American College of Physicians. All Rights Reserved.

< 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

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

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

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

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

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.

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

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.

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

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

• 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.)

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

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

• 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.)

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

Peritoneal Dialysis (cont.)
• Peritoneal Dialysis Diet
– Limit salt and fluid intake
– Consume more protein
– Some potassium restrictions
– Reduce caloric intake
• Complications
– Peritonitis

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

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%

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

64
• 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

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

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

67
• 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

68
• Modifiable
– HbA1c, BP & total cholesterol (Odds Ratio 43)
– Obesity, smoking
• Non-modifiable
– Age, ethnicity, male sex

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

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

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

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

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

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

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)

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%

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

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

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)

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

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
◦ 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

Diabetes
1,2 3 4 5
Time
GFR
Creat

Problems
 Precautions
 Blood pressure control
 Dietary protein restriction
 Management of MBD
 Management of anemia
 Vaccination
 Volume control
 Cardiovascular disease screening
 Options of renal replacement

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

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

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

Secondary
hyperparathyroidism
89

90
Decreased GFR
Hyperphosphatemia
Hypocalcemia
Low vitamin D
+
decreased activation
+
Resistance
Secondary hyperparathyroidism
Binders
Phosphate binder
+/-
Calcium supplement
Vitamin D/ analogues
Calcimimetics

91
Decreased GFR
Hyperphosphatemia
Hypocalcemia
Low vitamin D
+
decreased activation
+
Resistance
Binders
Phosphate binder
+/-
Calcium supplement
Vitamin D/ analogues
Calcimimetics

 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.

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

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

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

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

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

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

A clinical syndrome
DM +
Persistent albuminuria, Worsening
proteinuria, Hypertension &
progressive renal failure

Diabetic nephropathy (DN) is a major
cause of ESRD, and the incidence of
diabetes
mellitus is rising rapidly.

 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.

Effect of Angiotensin Blockade
Afferent arteriole
Efferent arteriole
Glomerular pressure
( GFR)
Glomerulus
Bowman’s Capsule
Angiotensin II
Proteinuria
A II blockade:

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)

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
hemodynamic effects
Reduce glomerular hypertrophy
well tolerated apart from hyperkalemia &
worsening of anemia in severe CRF
Cautious use in presence of severe renovascular
disease

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

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.

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.

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.

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

Clinical syndrome characterised by
persistent albuminuria (>300mg/24hrs)
on at least 2 occasions separated by
3 months.

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 infection
 Fluid loading
 Pregnancy

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 in
increased:
Vascular Contractility
Blood Flow
Cellular Proliferation
Vascular Permeability

Inhibition of PKC by
Ruboxistaurin in Rats
 Reduces Glomerular Hyperfiltration
 Albuminuria
 Extra cellular Matrix accumulation

Mechanisms for the Renoprotective
Effect of ACE Inhibitors
 Lower Systemic Blood Pressure
 Lower Intra glomerular Pressure and
filtration rates
 Reduce Proteinuria

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

Reduction in Oxidative Stress
Inhibit macrophage activation,
proliferation and migration

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

Hyperglycemia
Genetic factors
Hypertension control
from T. Hostetter

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

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 death, dialysis and transplantation in ACEI group
independent of BP
Lewis et al. NEJM, 1993

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

Hyperglycemia
Genetic factors
Effect of ACEIs and ARBs
from T. Hostetter

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

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 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

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 8.4 to 9.5 3.5 to 5.5 150 to 300
*Corrected calcium

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

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

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

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

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

Options of renal replacement
• Hemodialysis
• Peritoneal dialysis
• Renal transplantation

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

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

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

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.

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

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

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.

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)

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

Effect of statins
from T. Hostetter
Hyperglycemia
ROS
Genetic factors

• 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

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

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)

Obese, sedentary, “wrong diet”, genetic predisposition,…….
IGT
DM
Incipient Nephropathy
Overt or Clinical Nephropathy
ESRD
Progression of Nephropathy (2)

• 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….

Diabetic Nephropathy Treatment and Management

Diabetic Nephropathy Treatment and Management

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