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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.

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
  • Transcript

    • 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. 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. Causes of ESRF GN 14% Others 13% Hypertension 29% Diabetes 44% Report from US Renal Data
    • 4. Diabetes and high BP affect similar patients  Risk factors  Similar patients  Coexistence Hypertension in diabetes
    • 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. 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. Hypertension-induced tissue injury  Glomeruli generally spared  Involves stretch-induced tissue fibrosis  Upregulation of intercellular adhesion molecules
    • 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. Effects of proteinuria By containing toxic/inflammatory systems  Complement  Lipoproteins  Iron species  Protein overload of tubules
    • 10. Proteinuria should be considered a target for therapy as well as a risk marker for progressive loss of renal function
    • 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. 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. 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. 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. 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. Increased dietary proteins inducing hyperfiltration
    • 17. Increased dietary proteins inducing hyperfiltration  Hormonal effects Glucagons IGF1 Kinins Angiotensin II
    • 18. Increased dietary proteins inducing hyperfiltration  Hormonal effects Glucagons IGF1 Kinins Angiotensin II  Tubuloglomerular feedback
    • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.  The burden of renal disease  Identifying therapy that arrests progression  Choice of therapy RCT-based All others
    • 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. 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. 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. 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. How much important is BP control ?
    • 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. “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. “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. “People with mild benign hypertension with levels up to 210/110 need not be treated” 1946 Textbook - Diseases of the Heart, Friedberg
    • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. PLUS PL US PLUS
    • 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. 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. 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. 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. 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. 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. 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. 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. 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. FIN
    • 63. Hyperkalaemia when blocking the RAS  Is dietary K restricted  How much is the 24-hr urine K  Consolidate diuretic therapy  Discontinue therapy ?
    • 64. Limitations of hyperkalaemia and increased serum creatinine when blocking the RAS
    • 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. 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.  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. 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. 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. Diabetes in the adult population Diabetes Care 1998;21:1414-1431
    • 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. 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. 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. 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. 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. 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. (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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