Declaration of transparency
The presenter declares no conflict of interest

renoprotection in hypertensive
patients with d...
The global burden of CKD

 In the USA estimated 80,000 diagnosed yearly
 Affects >26M adults
 Additional 20M are at inc...
Causes of ESRF

GN
14%

Others
13%

Hypertension
29%

Diabetes
44%

Report from US Renal Data
Diabetes and high BP affect similar patients

 Risk factors
 Similar patients
 Coexistence

Hypertension in diabetes
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Hypertension-induced tissue injury

 Glomeruli generally spared
 Involves stretch-induced tissue fibrosis
 Upregulation...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Effects of proteinuria
By containing toxic/inflammatory systems

 Complement
 Lipoproteins
 Iron species
 Protein over...
Proteinuria should be considered a target for
therapy as well as a risk marker for progressive
loss of renal function
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Effect of excess angiotensin II
 Induces glomerular
hypertension and hypertrophy
 Induces mitogens viz PDGF
 Fibrosis t...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Hyperglycaemia causing DN


Increase in mesangial cell
proliferation and hypertrophy



Increased mesangial cell
product...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Increased dietary proteins inducing
hyperfiltration
Increased dietary proteins inducing
hyperfiltration
 Hormonal effects
Glucagons
IGF1
Kinins
Angiotensin II
Increased dietary proteins inducing
hyperfiltration
 Hormonal effects
Glucagons
IGF1
Kinins
Angiotensin II

 Tubuloglome...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Blood lipids
 MDRD study showed that high LDL C was an independent
risk factor for progression
 High cholesterol and TG ...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Smoking and CKD
 Tobacco smoking increases GFR through hyperfiltration
 Leads to elevated BP and loss of nocturnal dippi...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
Mechanisms of renal disease progression
 Hypertension

 Increased plasma homocysteine

 Proteinuria

 Increased endoge...
 The burden of renal disease
 Identifying therapy that arrests progression
 Choice of therapy
RCT-based
All others
Theoretical curve demonstrating the large beneficial
effects measured in years off dialysis
100

ml/m
i

n/yr

60

in
/

y...
Theoretical curve demonstrating the large beneficial
effects measured in years off dialysis
100

ml/m
i

n/yr

60

in
/

y...
Theoretical curve demonstrating the large beneficial
effects measured in years off dialysis
100

ml/m
i

n/yr

60

in
/

y...
Theoretical curve demonstrating the large beneficial
effects measured in years off dialysis
100

ml/m
i

n/yr

60

in
/

y...
How much important is BP control ?
“Hypertension may be an important
compensatory mechanism which
should not be tampered with, even
were it certain that we c...
“The greatest danger to a man with
high blood pressure lies in its discovery,
because then some fool is certain to try
and...
“The greatest danger to a man with
high blood pressure lies in its discovery,
because then some fool is certain to try
and...
“People with mild benign hypertension with
levels up to 210/110 need not be treated”

1946 Textbook - Diseases of the Hear...
“People with mild benign hypertension with
levels up to 210/110 need not be treated”
“There is a psychopathologic personal...
Control of BP, MDRD results


Low BP goal (mean 125/75) slowed
progression better than usual goal
(135/85)
10



The gre...
eGFR (mL/min/1.73 m2) per y

Relationship Between Achieved BP
and GFR
95

98

101

104

107

110

113

116

119

0
-2

ESR...
comparison of tight BP control and tight sugar control
on CV outcomes UKPDS 38 trial
stroke

Any diabetic endpoint

DM dea...
Goal BP in diabetes
Results of ACCORD


4733 type 2 D pts
intensive <120 or
standard therapy <140



There was no differ...
Benefits Beyond Blood Pressure Control: Primary
Composite Endpoint
Doubling of SCr / ESRD / Death

50

% with event

40
30...
Why is the dissociation
 Substantially high AII concentration within the kidney as compared
to the systemic circulation
C...
Glycaemia control to slow progression
 Reversal of glomerular hypertrophy and hyperfiltration
 Delayed development of el...
Reduced dietary protein
 Restrict protein intake to 0.6G/Kg/24 hrs
 Make allowance to those with heavy proteinuria
 Slo...
Other measures to slow progression of renal
disease
 Control homocysteine level
 smoking
 Control hyperinsulinaemia
 C...
Other measures to slow progression of renal
disease
 Control homocysteine level
 smoking
 Control hyperinsulinaemia
 C...
Other measures to slow progression of renal
disease
 Control homocysteine level
 smoking
 Control hyperinsulinaemia
 C...
PLUS

PL

US

PLUS
Other measures to slow progression of renal
disease
 Control homocysteine level
 smoking
 Control hyperinsulinaemia
 C...
Other measures to slow progression of renal
disease
 Control homocysteine level
 smoking
 Control hyperinsulinaemia
 C...
Other measures to slow progression of renal
disease
 Control homocysteine level
 smoking
 Control hyperinsulinaemia
 C...
Other measures to slow progression of renal
disease
 Control homocysteine level
 smoking
 Control hyperinsulinaemia
 C...
Other measures to slow progression of renal
disease
 Control homocysteine level
 smoking
 Control hyperinsulinaemia
 C...
Other measures to slow progression of renal
disease
 Control homocysteine level
 smoking
 Control hyperinsulinaemia
 C...
Hazard ratio for CV events

Graded and independent relationship between
eGFR and CVD outcomes

eGFR (mL/min/1.73 sm
Adjust...
Conclusion 1
 The combination of hypertension and diabetes is nefarious and leads
to increased complications
 Progressio...
Conclusion 2

 Multiple risk-factor intervention strategy is the best to adopt in patients
with CKD
 Control of BP is of...
FIN
Hyperkalaemia when blocking the RAS
 Is dietary K restricted
 How much is the 24-hr urine K
 Consolidate diuretic thera...
Limitations of hyperkalaemia and increased
serum creatinine when blocking the RAS
Effect of ACEI and B blockers in Type I diabetes
0
-2

0

6

12

18

24

30

36

Decline in GFR (ml/min)

-4
-6
-8
b block...
Effect of ACEI and B blockers in Type I diabetes
0
-2

0

6

12

18

24

30

36

Decline in GFR (ml/min)

-4
-6
-8
b block...
 1.1% of Australians have a S Cr level >120 umol/L
(1.36 mg%)
 2.5% of Australian adults age 25 yrs or more have
signifi...
Cardiovascular Deaths in ESRD Patients
100

Annual Mortality (%)

10

Dialysis Male
Dialysis Female
Dialysis Black
Dialysi...
Interaction of HT, proteinuria and GFR loss
1

Decrease HT

5

Decrease proteinuria

3

2

4
6

Decrease glomerular
injury...
Diabetes in the adult population

Diabetes Care 1998;21:1414-1431
prevalence of hypertension
x1000

1600
1400

Hypertension is one of the
most prevalent cardiovascular
.diseases

1200
1000...
age-specific prevalence of the metabolic syndrome
50
45

Prevalence (%)

40
35
Men

30

Women

25
20
15
10
5
0
20-29

30-3...
8-yr-incidence of diabetes amongst normo
and hypertensive individuals

30
Incidence of diabetes
(cases/1000 person-years)
...
CV mortality and systolic pressure in diabetics and nondiabetic

CV mortality rate per 10 000 person-yrs

275
250
225
200
...
Interaction of HT, proteinuria and GFR loss
1

Decrease HT

5

Decrease proteinuria

3

2

4
6

Decrease glomerular
injury...
Change from Baseline in Proteinuria

Median % change

40
20
0

35%

–20
–40

35% overall reduction
p<0.001

–60
0

12

24
...
(RENAAL STUDY (ESRD

% with event

30

20

10

28%
Risk reduction: 28%
p=0.002

0
0

12

24

36

48

Months of study
Place...
Renoprotection in hypertensive patients with diabetes
Renoprotection in hypertensive patients with diabetes
Renoprotection in hypertensive patients with diabetes
Renoprotection in hypertensive patients with diabetes
Renoprotection in hypertensive patients with diabetes
Renoprotection in hypertensive patients with diabetes
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Renoprotection in hypertensive patients with diabetes

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DM and Hypertension is a nasty combination for the health of the kidneys. Control of both diseases is crucial for renoprtection.

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  • The CaR is the principal regulator of PTH secretion.
    Activation of the CaR by an increase in extracellular calcium produces a rapid decrease in PTH secretion—occurring within minutes or hours. A decrease in extracellular calcium produces a rapid increase in PTH secretion.
    In contrast, vitamin D sterols inhibit PTH production rather than secretion, and response to therapy with vitamin D sterols is therefore slower than response to calcium.
  • The primary endpoint of RENAAL was the time to the first event of the composite endpoint of doubling of serum creatinine concentration, ESRD (defined by the need for long-term dialysis or renal transplantation), or death. In the primary intention-to-treat (ITT) data analysis, losartan + conventional therapy produced a significant risk reduction of 16% (p=0.02).1
  • A key inclusion criterion of the RENAAL trial was proteinuria. In this study, proteinuria was defined by the urinary albumin:creatinine ratio determined from first morning specimens of urine. This slide shows the dramatic effects of losartan + conventional therapy in reducing proteinuria in patients with type 2 diabetes. In the placebo + conventional therapy treatment group, proteinuria tended to increase.1
  • This slide shows one component of the composite primary endpoint, development of ESRD (defined in this study as the need for long-term dialysis or renal transplantation). Once-daily losartan + conventional therapy significantly reduced the risk of development of ESRD by 28% (p=0.002). Doubling of serum creatinine, another important renal endpoint, was also significantly reduced by 25% with losartan + conventional therapy (p=0.006). The composite endpoint of ESRD or death also showed a significant risk reduction (20%; p=0.01). There was no significant risk reduction of death alone with losartan + conventional therapy.1
  • Renoprotection in hypertensive patients with diabetes

    1. 1. Declaration of transparency The presenter declares no conflict of interest renoprotection in hypertensive patients with diabetes Mustafa Nur Elhuda Khartoum Feb. 20th 2014
    2. 2. The global burden of CKD  In the USA estimated 80,000 diagnosed yearly  Affects >26M adults  Additional 20M are at increased risk of developing CKD  9th cause of death
    3. 3. Causes of ESRF GN 14% Others 13% Hypertension 29% Diabetes 44% Report from US Renal Data
    4. 4. Diabetes and high BP affect similar patients  Risk factors  Similar patients  Coexistence Hypertension in diabetes
    5. 5. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    6. 6. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    7. 7. Hypertension-induced tissue injury  Glomeruli generally spared  Involves stretch-induced tissue fibrosis  Upregulation of intercellular adhesion molecules
    8. 8. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    9. 9. Effects of proteinuria By containing toxic/inflammatory systems  Complement  Lipoproteins  Iron species  Protein overload of tubules
    10. 10. Proteinuria should be considered a target for therapy as well as a risk marker for progressive loss of renal function
    11. 11. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    12. 12. Effect of excess angiotensin II  Induces glomerular hypertension and hypertrophy  Induces mitogens viz PDGF  Fibrosis through TGF or ET1  Ammonia formation  Inflammatory intracellular signaling mechanisms  Increases tubular absorption of Na  Increases oxidant stress  Increases aldosterone  Increases expression of monocyte chemoattractant protein  Increases PAI1
    13. 13. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    14. 14. Hyperglycaemia causing DN  Increase in mesangial cell proliferation and hypertrophy  Increased mesangial cell production  Basement membrane thickening  Mesangial cell apoptosis  Upregulation VEGF expression in podocytes  High glucose level  Glycosylation  Protein kinase C  Aldose reductase pathway
    15. 15. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    16. 16. Increased dietary proteins inducing hyperfiltration
    17. 17. Increased dietary proteins inducing hyperfiltration  Hormonal effects Glucagons IGF1 Kinins Angiotensin II
    18. 18. Increased dietary proteins inducing hyperfiltration  Hormonal effects Glucagons IGF1 Kinins Angiotensin II  Tubuloglomerular feedback
    19. 19. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    20. 20. Blood lipids  MDRD study showed that high LDL C was an independent risk factor for progression  High cholesterol and TG promote progression of diabetic glomerulosclerosis  In ARIC study, low HDL C and high TG independent risk factors for significant increase in S Cr
    21. 21. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    22. 22. Smoking and CKD  Tobacco smoking increases GFR through hyperfiltration  Leads to elevated BP and loss of nocturnal dipping  Increases aldosterone level  Enhances platelet aggregation leading to injury of renal endothelial cells  Higher risk for developing albuminuria in diabetics  Rate of progression of diabetic nephropathy increases  In the nondiabetic, smokers had a dose-dependent increase in risk for developing ESRD
    23. 23. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    24. 24. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    25. 25. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    26. 26. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    27. 27. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    28. 28. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    29. 29. Mechanisms of renal disease progression  Hypertension  Increased plasma homocysteine  Proteinuria  Increased endogenous insulin  Excess AII  Hyperphosphataemia  Hyperglycaemia  Anaemia  Increased dietary protein  Excess aldosterone  hyperlipidaemia  K depletion  Cigarette smoking  Increased level of procoagulants
    30. 30.  The burden of renal disease  Identifying therapy that arrests progression  Choice of therapy RCT-based All others
    31. 31. Theoretical curve demonstrating the large beneficial effects measured in years off dialysis 100 ml/m i n/yr 60 in / yr ml /m in/ y age ml/m in 45 1 / yr 1 r2 5 40 m l/m ng a t 3 yr in/ /m ml GFR ml/min/1.73 m2 80 star ti 20 ESRD ESRD 0 25 35 45 Age in years 55 65 75 Adapted from Hebert LA,Wilmer WA etc
    32. 32. Theoretical curve demonstrating the large beneficial effects measured in years off dialysis 100 ml/m i n/yr 60 in / yr ml /m in/ y age ml/m in 45 1 / yr 1 r2 5 40 m l/m ng a t 3 yr in/ /m ml GFR ml/min/1.73 m2 80 star ti 20 ESRD ESRD 0 25 35 45 Age in years 55 65 75 Adapted from Hebert LA,Wilmer WA etc
    33. 33. Theoretical curve demonstrating the large beneficial effects measured in years off dialysis 100 ml/m i n/yr 60 in / yr ml /m in/ y age ml/m in 45 1 / yr 1 r2 5 40 m l/m ng a t 3 yr in/ /m ml GFR ml/min/1.73 m2 80 star ti 20 ESRD ESRD 0 25 35 45 Age in years 55 65 75 Adapted from Hebert LA,Wilmer WA etc
    34. 34. Theoretical curve demonstrating the large beneficial effects measured in years off dialysis 100 ml/m i n/yr 60 in / yr ml /m in/ y age ml/m in 45 1 / yr 1 r2 5 40 m l/m ng a t 3 yr in/ /m ml GFR ml/min/1.73 m2 80 star ti 20 ESRD ESRD 0 25 35 45 Age in years 55 65 75 Adapted from Hebert LA,Wilmer WA etc
    35. 35. How much important is BP control ?
    36. 36. “Hypertension may be an important compensatory mechanism which should not be tampered with, even were it certain that we could control it.” Paul Dudley White, 1931
    37. 37. “The greatest danger to a man with high blood pressure lies in its discovery, because then some fool is certain to try and reduce it.” Hay, Brit Med J, 1931
    38. 38. “The greatest danger to a man with high blood pressure lies in its discovery, because then some fool is certain to try and reduce it.” Don’t approach a goat from the front , a horse from the back or a fool from any side Hay, Brit Med J, 1931
    39. 39. “People with mild benign hypertension with levels up to 210/110 need not be treated” 1946 Textbook - Diseases of the Heart, Friedberg
    40. 40. “People with mild benign hypertension with levels up to 210/110 need not be treated” “There is a psychopathologic personality associated with hypertension” 1946 Textbook - Diseases of the Heart, Friedberg
    41. 41. Control of BP, MDRD results  Low BP goal (mean 125/75) slowed progression better than usual goal (135/85) 10  The greater the proteinuria the greater was the benefit of achieving the low BP goal 9 8 7 6 5  Achieved systolic BP predicted decline better than achieved diastolic BP low BP usual BP 4 3 2 1 0 <1gday  The low BP goal did not significantly slow GFR decline in those with proteinuria <1G/24 hrs 1-2.9g/day >=3g/day Data from Klahr, S, Levey, AC, Beck, GJ,, et al, N Engl J Med 1994; 330:807
    42. 42. eGFR (mL/min/1.73 m2) per y Relationship Between Achieved BP and GFR 95 98 101 104 107 110 113 116 119 0 -2 ESRD in 20 -30 years -4 r =0.69 p <0.05 untreated HT -6 -8 -10 -12 130/80 140/90 ESRD in 5-6 years -14 *MAP = [SBP + (2 × DBP)]/3 mm Hg. Summary of 9 studies used in figure (3 in non-diabetics). Parving et al. 1989; Viberti et al. 1993; Klahr et al. 1993; Hebert et al. 1994; Lebovitz et al. 1994; Moschio et al. 1996; Bakris et al. 1996; Bakris et al. 1997; GISEN Group. 1997. Bakris et al. Am J Kidney Dis. 2000;36:646-661.
    43. 43. comparison of tight BP control and tight sugar control on CV outcomes UKPDS 38 trial stroke Any diabetic endpoint DM death Microvascular complications 0 -10 %Change in risk -20 * -30 * -40 -50 * * Tight glucose control Tight blood pressure control Tight BP control and risk of macrovascular and microvascularComplications in type II diabetes: UKPDS 38. UK prospective diabetes Study Group. BMJ. 1998;317:703 P < 0.05 as compared with tight glucose control*
    44. 44. Goal BP in diabetes Results of ACCORD  4733 type 2 D pts intensive <120 or standard therapy <140  There was no difference in the annual rate of the primary composite outcomes  There was no difference in the annual allcause mortality rate or in the rate of death  Intensive therapy was associated with significant reduction in the annual rate of total stroke and nonfatal stroke  Serious adverse events attributable to antihypertensive drugs occurred significantly more frequently in the intensive therapy
    45. 45. Benefits Beyond Blood Pressure Control: Primary Composite Endpoint Doubling of SCr / ESRD / Death 50 % with event 40 30 16% 20 10 Risk reduction: 16% p=0.02 0 0 12 24 36 48 Months of study Placebo (+CT) 762 Losartan (+CT) 751 689 692 554 583 295 329 36 52 Adapted from Brenner BM et al N Engl J Med 2001;345(12):861–869; Brenner B. Presented at 16th Annual Meeting of the American Society of Hypertension, San Francisco, CA, USA, May 16–19, 2001.
    46. 46. Why is the dissociation  Substantially high AII concentration within the kidney as compared to the systemic circulation Chronic interstitial hypoxia Interstitial infiltration of inf. cells Iron deposition Activation of PAI 1  Alternative view Inhibition of formation of AGEs Inhibition of oxidative stress
    47. 47. Glycaemia control to slow progression  Reversal of glomerular hypertrophy and hyperfiltration  Delayed development of elevated albumin excretion  Stabilization or decrease protein excretion  Effect of pancreas transplantation  Transplantation of donor kidney with diabetic nephropathy
    48. 48. Reduced dietary protein  Restrict protein intake to 0.6G/Kg/24 hrs  Make allowance to those with heavy proteinuria  Slows progression by 0.5ml/min/yr  In MDRD, benefit occurred in patients with GFR between 12.5-55 ml/min  For each G reduction in proteinuria observed at 4 months, GFR was slowed by 1 ml/min/yr
    49. 49. Other measures to slow progression of renal disease  Control homocysteine level  smoking  Control hyperinsulinaemia  Correct anaemia  Use of antioxidants  Avoid hypokalaemia  Control hyperphosphataemia  Low dose aspirin
    50. 50. Other measures to slow progression of renal disease  Control homocysteine level  smoking  Control hyperinsulinaemia  Correct anaemia  Use of antioxidants  Avoid hypokalaemia  Control hyperphosphataemia  Low dose aspirin
    51. 51. Other measures to slow progression of renal disease  Control homocysteine level  smoking  Control hyperinsulinaemia  Correct anaemia  Use of antioxidants  Avoid hypokalaemia  Control hyperphosphataemia  Low dose aspirin
    52. 52. PLUS PL US PLUS
    53. 53. Other measures to slow progression of renal disease  Control homocysteine level  smoking  Control hyperinsulinaemia  Correct anaemia  Use of antioxidants  Avoid hypokalaemia  Control hyperphosphataemia  Low dose aspirin
    54. 54. Other measures to slow progression of renal disease  Control homocysteine level  smoking  Control hyperinsulinaemia  Correct anaemia  Use of antioxidants  Avoid hypokalaemia  Control hyperphosphataemia  Low dose aspirin
    55. 55. Other measures to slow progression of renal disease  Control homocysteine level  smoking  Control hyperinsulinaemia  Correct anaemia  Use of antioxidants  Avoid hypokalaemia  Control hyperphosphataemia  Low dose aspirin
    56. 56. Other measures to slow progression of renal disease  Control homocysteine level  smoking  Control hyperinsulinaemia  Correct anaemia  Use of antioxidants  Avoid hypokalaemia  Control hyperphosphataemia  Low dose aspirin
    57. 57. Other measures to slow progression of renal disease  Control homocysteine level  smoking  Control hyperinsulinaemia  Correct anaemia  Use of antioxidants  Avoid hypokalaemia  Control hyperphosphataemia  Low dose aspirin
    58. 58. Other measures to slow progression of renal disease  Control homocysteine level  smoking  Control hyperinsulinaemia  Correct anaemia  Use of antioxidants  Avoid hypokalaemia  Control hyperphosphataemia  Low dose aspirin
    59. 59. Hazard ratio for CV events Graded and independent relationship between eGFR and CVD outcomes eGFR (mL/min/1.73 sm Adjusted for baseline age, sex, income, education, coronary disease, chronic heart failure, stroke or transient ischemic attack, peripheral artery disease, diabetes, hypertension, dyslipidemia, cancer, hypoalbuminemia, dementia, liver disease, proteinuria, prior hospitalizations, and subsequent dialysis requirement. Shastri S et al. Am J Kidney Dis. 2010 Jul 2. [Epub ahead of print].
    60. 60. Conclusion 1  The combination of hypertension and diabetes is nefarious and leads to increased complications  Progression of a variety of CKD is largely due to secondary haemodynamic and metabolic factors rather than the activity of the underlying disease  Proteinuria as such promotes the progression of renal disease  Proteinuria should be considered a target for therapy as well as a risk marker for progressive loss of renal function  Patients with APKD merit special consideration with regard to aspirin and BP control
    61. 61. Conclusion 2  Multiple risk-factor intervention strategy is the best to adopt in patients with CKD  Control of BP is of paramount importance in slowing down the progression of CKD  Control of BP is more important in slowing the progression of CKD than control of blood sugar in patients with type II diabetes and proteinuria  In patients with CKD, AII blockers give benefit beyond BP control
    62. 62. FIN
    63. 63. Hyperkalaemia when blocking the RAS  Is dietary K restricted  How much is the 24-hr urine K  Consolidate diuretic therapy  Discontinue therapy ?
    64. 64. Limitations of hyperkalaemia and increased serum creatinine when blocking the RAS
    65. 65. Effect of ACEI and B blockers in Type I diabetes 0 -2 0 6 12 18 24 30 36 Decline in GFR (ml/min) -4 -6 -8 b blocker -10 acei -12 -14 -16 -18 -20 Months (Graph adapted from studies from DCCT, (Diabetes Complications and Control Trial
    66. 66. Effect of ACEI and B blockers in Type I diabetes 0 -2 0 6 12 18 24 30 36 Decline in GFR (ml/min) -4 -6 -8 b blocker -10 acei -12 -14 -16 -18 -20 Months (Graph adapted from studies from DCCT, (Diabetes Complications and Control Trial
    67. 67.  1.1% of Australians have a S Cr level >120 umol/L (1.36 mg%)  2.5% of Australian adults age 25 yrs or more have significant proteinuria  Screening in Japan indicates that people with protienuria are 15 times more likely than those without proteinuria to develop renal failure within 10 yrs
    68. 68. Cardiovascular Deaths in ESRD Patients 100 Annual Mortality (%) 10 Dialysis Male Dialysis Female Dialysis Black Dialysis White GP Male GP Female GP Black GP White 1 0.1 0.01 25-34 35-44 45-54 55-64 65-74 Age (years) Foley R et al. Am J Kidney Dis, p S115, 1998 75-84 >85
    69. 69. Interaction of HT, proteinuria and GFR loss 1 Decrease HT 5 Decrease proteinuria 3 2 4 6 Decrease glomerular injury 8 Decrease tubular injury 9 7 Decrease GFR loss Reprinted from Hebert et al
    70. 70. Diabetes in the adult population Diabetes Care 1998;21:1414-1431
    71. 71. prevalence of hypertension x1000 1600 1400 Hypertension is one of the most prevalent cardiovascular .diseases 1200 1000 800 In the USA )out of 3 (35 – 64 Y 1 600 400 200 European Countries out of 2 (55% 1 )prevalence 0 2008 2025 Wolf-Mair, JAMA 2003 - 239
    72. 72. age-specific prevalence of the metabolic syndrome 50 45 Prevalence (%) 40 35 Men 30 Women 25 20 15 10 5 0 20-29 30-39 40-49 50-59 Age (years) 60-69 >69 (From NHANES-111 (1988-1994
    73. 73. 8-yr-incidence of diabetes amongst normo and hypertensive individuals 30 Incidence of diabetes (cases/1000 person-years) 20 10 0 Normo (n=8746) Hyper (n=3804) New Engl J Med 2000; 342:905-912
    74. 74. CV mortality and systolic pressure in diabetics and nondiabetic CV mortality rate per 10 000 person-yrs 275 250 225 200 175 150 Without diabetes With diabetes 125 100 75 50 25 0 <120 120-139 140-159 160-179 SYSTOLIC BP 180-199 >200 Adapted from Stamler J et al Diabetes Care 1993;16(2):435-444
    75. 75. Interaction of HT, proteinuria and GFR loss 1 Decrease HT 5 Decrease proteinuria 3 2 4 6 Decrease glomerular injury 8 Decrease tubular injury 9 7 Decrease GFR loss Reprinted from Hebert et al
    76. 76. Change from Baseline in Proteinuria Median % change 40 20 0 35% –20 –40 35% overall reduction p<0.001 –60 0 12 24 36 48 Months of study Placebo (+CT) 762 Losartan (+CT) 751 632 661 529 558 Proteinuria measured as the urinary albumin-to-creatinine ratio in a first morning specimen Adapted from Brenner BM et al N Engl J Med 2001;345(12):861–869. 390 438 130 167
    77. 77. (RENAAL STUDY (ESRD % with event 30 20 10 28% Risk reduction: 28% p=0.002 0 0 12 24 36 48 Months of study Placebo (+CT) Losartan (+CT) 762 751 715 714 Adapted from Brenner BM et al N Engl J Med 2001;345(12):861–869. 610 625 347 375 42 69
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