Diabetic nephropathy management

1. Diabetic Nephropathy: “ You can't cure it so you have to endure it ” BY DR.KARTHIK.RAO.N

2. Current Terminology Kidney, not Renal (or Reno) CKD, not CRF DKD (= diabetic nephropathy) AKI, not ARF Still ESRD (End Stage Renal Disease) Still RRT (Renal Replacement Therapy)

3. 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 m 2 , with or without kidney damage

4. Definition and Problem Progressive  in UAE a/w  BP and  GFR 35-50% DN in Type 1 after 20 years of disease 10- ? 20% DN Type 2 in patients on diagnosis ?? Renal risk is equal in both Type I and II DM Progressive rise in ESRD: Up to 40% of patients on RRT due to DN Strong association with cardiovascular risk (20-40 fold higher)

5. Stages of Chronic Kidney Disease Stage Description GFR (mL/min) 1 Kidney damage ± normal or  GFR ≥90 2 Kidney damage ± mild  GFR 60-89 3 Moderate  GFR 30-59 4 Severe  GFR 15-29 5 Kidney Failure <15 Use e-GFR and not S Creat in practice

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

7. Diagnosis Hyperfiltration Clinical Latency Microalbuminuria Macroalbuminuria Renal failure Diabetes Microalbuminuria Dipstick negative Macroalbuminuria Dipstick positive 30 300 mg/d New Terminology Micro-albuminuria = High Albuminuria Macroabuminurai = Very high Albuminuria

8. Stage of hyper- filtration Micro albumi- nuria Macro albumi- nuria Azotemia (Renal failure) End stage Renal disease Normo albumi- nuria NATURAL HISTORY OF NEPHROPATHY IN TYPE 1 DIABETES 15 - 20 yrs 1 yrs 4 - 5 yrs

9. Natural History

10. Type II Microalbuminuria Macroalbuminuria Renal failure Diagnosis Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Diagnosis Hyperfiltration Clinical Latency Microalbuminuria Macroalbuminuria Renal failure Type 1

11. Definitions of abnormalities in albumin excretion Because of variability in urinary albumin excretion, two of three specimens collected within a 3- to 6-month period should be abnormal before considering a patient to have crossed one of these diagnostic thresholds. Exercise within 24h, infection, fever, congestive heart failure, marked hyperglycemia, marked hypertension, pyuria , and hematuria may elevate urinary albumin excretion over baseline values. Diabetes care 2004; 27(1): S79-S83

12. Type II Macroalbuminuria Renal failure Diagnosis Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Diagnosis Hyperfiltration Clinical Latency Microalbuminuria Macroalbuminuria Renal failure Type 1

13. Type II Renal failure Diagnosis Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Diagnosis Hyperfiltration Clinical Latency Microalbuminuria Macroalbuminuria Renal failure Type 1

14. Microalbuminuria & Proteinuria Normal Microalbuminuria Overt proteinuria F M F M Albumin/creatinine ratio (mg/mmol) <3.5 <2.5 >3.5 >2.5 >30 Equivalent Albumen excretion (mg/day) <30 30-300 300 Diagnosis of microalbuminuria based on 2 out of 3 urine samples in absence of UTI After 5 years of Dx in T1DM & than annually. At the time of diagnosis in T2DM.

15. U/A at Diagnosis (Type 2 patients) Random spot collection Albumin:creatinine Repeat 3x in 3-6 months 2 of 3 ≥ 30mg/g creatinine Microalbuminuria, begin treatment Nephropathy Quantify µalb:Cr Consider referral No microalbuminuria Re-screen yearly Negative Positive No Yes

16. 16 What are Diabetics with Nephropathy Dying From? Stroke Myocardial Infarction Heart Failure Sudden Death

17. Risk Factors : Non Modifiable Race : Indo-Asians, Africans, Hispanics, Native Americans. Familial clustering: In Type 1 DM if 1* relative > 80% chances of developing DN. In Type 2 DM (Pima Indians) 14%, 23% and 46% (0,1,2 parents DM) Genetic influence ACE gene polymorphism ( DD in Type 2) Ag-II type 2 receptor gene (AT2) on X-chromosome. (AA haplotype  risk than GT haplotype in type 1 DM) Inheritance of one allele of the aldose reductase gene, Low Birth weight Age Type 1 onset < 5  risk of ESRD but risk  in T2DM in Pima indians <20 yrs. Type 1 no proteinuria till age 25 risk <1 % Elevated pro-renin levels .

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

19. Natural History in Type 2 DM GFR decline once proteinuria present 12 ml/min/year untreated Patients often die of other causes (CVS disease) before ESRF CVS risk rises 2-3X with microalbuminuria, 9-10X with clinical proteinuria Higher rates of ESRF in T1DM

20. Hypertension Greater than 140/90 increases the risk of diabetes 50-60% of newly diagnosed patients also have HTN at diagnosis An interesting note: A family history of HTN in a child with Type 1 diabetes  their risk of developing nephropathy

21. Undesirable lipid levels HDL less than 35 mg/dL Triglycerides greater than 150 mg/dL Think diabetes or hypothyroidism with the above lipid profile Draw a FBS and a TSH

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

23. Hyperglycaemia Early histological lesions reversible with normoglycaemia Hypertension Predicts microalbimunuria,  proteinuria paralleled by gradual rise in BP Correlation between BP and rate of  of GFR Proteinuria Induces tubulointerstitial damage/ contributes to progression Highly selective in early disease Pathogenesis of DN

24. Oparil et al. Ann Intern Med 139:761-76, 2003. ANG II ANG II

25. Cross-talk between the Insulin and Aangiotensin- II Angiotensin II  insulin sensitivity & insulin secretion, explaining the antidiabetogenic effect of RAS blockade Hyperinsulinemia enhances Ang II-induced transcriptional activity in vascular smooth muscle cells

26. Treatment Glycemic control Blood pressure control Angiotensin 2 control Proteinuria control Cholesterol control

27. DCCT 1400 T1DM Intensive Conventional HbA1C 7.3% 9.1% Reduction in Retinopathy- 47% Microalbumnuria- 39% Clinical Nephropathy- 54% Neuropathy- 60% Benefits of intensive control persisted even after study concluded and glycemic control worsened. After 17 years 50% reduction in macrovascular complications .

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

29. Randomized prospective trial of treatment strategies in type II diabetes ukpds Type 2 diabetic patients 5,102 Person years follow-up 53,000 Intensive Conventional HbA1c 7% 7.9% At 12 years 23 % 34 % Each 1% decrease in HbA1C decreases microvascular complications by 35%. Macrovascular advantage is seen after 10 years. Strict BP control decreased microvascular complications .

30. Benefits of Glycemic Control Delay the development of  albumin excretion Stabilize or  protein excretion in pts with  UAE Slow the progressive renal injury in Macroalb. May reverse early structural changes UKPDS Study : Glycemic control is less than the benefit from blood pressure control

31. ACEi are good ARB are good What about both together?

32. 33 Ang I Ang II Progressive Diabetic Nephropathy ACE Renal Injury and Proteinuria ACEi AT 1 Receptor Non-ACE Pathways Aldosterone MRA ARB Can Dual Blockade of the RAAS Improve Renal Outcomes in Diabetic Nephropathy? + +

33. CALM Study N= 200 Type II DM with microalbuminuria Randomized to: Lisinopril 20 mg qd Candesartan 16 mg qd Combination of lisinopril 20 mg and candesartan 16 mg Mogensen CE, Et al. BMJ 2000; 321: 1440-4. Candesartan and Lisinopril Microalbuminuria (CALM)

34. Calcium channel blockers Verapamil does not delay development of microalbuminuria Verapamil does reduce proteinuria in diabetics independent of changes in BP. Side effect:  FGGS & TIF. Aldosterone antagonists Spironolactone reduces proteinuria in diabetics Change in proteinuria is independent of blood pressure All patients were treated with an ACEi or ARB 24-Hr ambulatory BP fell 6/2 Schjoedt KJ, Et al. Kidney International 2006; 70: 536-542.

35. 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 % 10 Primary endpoint 20 Ramipril (n = 8,576) 16.5 10 15 5 Mortality 11.6 12.5 11.8 % (p < 0.004*) (p = ns) * Telmisartan vs. ramipril for noninferiority

36. RENIN INHITORS PLUS ARBS/ACEI

37. 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

38. Treatment Blood pressure control Glycemic control Proteinuria control Cholesterol control

39. Protein restriction slows progression of DN

40. Is Anemia Causing Cardiovascular And Renal Disease In Diabetics, Or is it Just A Marker?

41. 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.

42. < 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

43. 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

44. 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

45. 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

46. 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

47. 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.

48. 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

49. 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.

50. Screening for Diabetic Nephropathy 1 American Diabetes Association: Nephropathy in Diabetes (Position Statement). Diabetes Care 27 (Suppl.1): S79-S83, 2004

51. 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

52. 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.)

53. 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

54. 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

55. 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.)

56. 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

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

58. 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

59. 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%

60. 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

61. 64 Diabetic Nephropathy From haemodynamic & metabolic stresses Metabolic stress deposition of advanced glycosylation end products in connective tissue & sml vessels. May take 10-20 yrs but many T2DM asymptomatic for several yrs, hence nephropathy may already be present at Dx

62. 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

63. 66 1 st 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

64. 67 Nephropathy Risk Factors DM Type & Duration 20% of Type I after 20 years 40% of Type II any duration Poor diabetic control Hypertension Aboriginal > Indian > Caucasian Smokers Family history

65. 68 Nephropathy Risk Factors Modifiable HbA1c, BP & total cholesterol (Odds Ratio 43) Obesity, smoking Non-modifiable Age, ethnicity, male sex

66. 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

67. 70 ACE Inhibitors can prevent progression of renal failure 120 160 200 240 280 320 350 400 80 1 2 3 4 5 6 Years Ann Intern Med 118 577-581.1993 Placebo Enalapril 85 90 95 100 105 110 80 1 2 3 4 5 6 Years Placebo Enalapril Normotensive Type 2 Diabetics Proteinuria (mg/day) % Initial GFR

68. 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 500 1000 2000 Jan 2000 2001 2002 Protein/Creat Ratio - Urine mg/mmol

69. 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 β -blockers better than ACE-I Rx NO

70. 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

71. 74 How can DM effect Dialysis? Autonomic neuropathy – may suffer hypotension increased by large fluid shift in HD Uncontrolled blood sugar s – 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

72. 75 Strict BSL Control in early Type I Target HbA 1 c < 7% For every 1% ↓ HbA 1 c: 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)

73. 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 HbA 1 c by 0.5-1%

74. 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

75. 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 + /H 2 0, ↑ vasc. permeability) Expensive

76. 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)

77. 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

78. Creatinine - it’s the best we have!

79. 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

80. Natural history of DN

81. Diabetes 1,2 3 4 5 Time GFR Creat

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

83. 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

84. 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

85. 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

86. Secondary hyperparathyroidism 89

87. 90 Decreased GFR Hyperphosphatemia Hypocalcemia Low vitamin D + decreased activation + Resistance Secondary hyperparathyroidism Binders Phosphate binder +/- Calcium supplement Vitamin D/ analogues Calcimimetics

88. 91 Decreased GFR Hyperphosphatemia Hypocalcemia Low vitamin D + decreased activation + Resistance Secondary hyperparathyroidism Binders Phosphate binder +/- Calcium supplement Vitamin D/ analogues Calcimimetics

89. Diabetic Nephropathy DN occurs in 35-40% of patients with type I diabetes (IDDM) whereas it occurs only in 15-20% of patients with type II diabetes (NIDDM). Definition or Criteria for diagnosis of DN Presence of persistent proteinuria in sterile urine of diabetic patients with concomitant diabetic retinopathy and hypertension.

90. 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

91. 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

92. 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

93. Vaccinations Hepatitis B 20 mcg each deltoid IM 0, 1, 2, 6 months Check Anti HBS titre post vaccination after 3 rd dose Only 60 % seroconvert in ESRD Pneumococcal vaccine Influenza vaccine

94. 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

95. 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 common

96. Diabetic Nephropathy A clinical syndrome DM + Persistent albuminuria, Worsening proteinuria, Hypertension & progressive renal failure

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

98. Diabetic Nephropathy DN occurs in 35-40% of patients with type I diabetes (IDDM) whereas it occurs only in 15-20% of patients with type II diabetes (NIDDM). Definition or Criteria for diagnosis of DN Presence of persistent proteinuria in sterile urine of diabetic patients with concomitant diabetic retinopathy and hypertension.

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

100. 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)

101. ARBs in NIDDM,HTN & microalbuminuria-Parving 2001

102. 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

103. DN: ADA Position Statement Screening: Perform an annual test for the presence of microalbuminuria in type 1 diabetic patients who have had diabetes > 5 years and 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

104. 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.

105. 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.

106. Treatment Objectives to Prevent Macrovascular Disease in Diabetic Patients Hypertension BP < 130/80 mmHg Hypercholesterolemia LDL < 100 mg/dL Hyperglycemia Hgb A 1C < 7.0 % American Diabetes Association Clinical Practice Recommendations. Diabetes Care. 2001;24(suppl1):S1-S133.

107. 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 A 1C to <7% Low salt diet (<2 gm NaCl/day) Stop cigarette smoking

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

109. Epidemiology Incidence of Diabetic Nephropathy in Type 1 Diabetes 4-17% 20 years 16-30% 30 years 30-40% 40 years

110. Epidemiology Incidence of Diabetic Nephropathy in Type 2 Diabetes 5% at diagnosis 20% after 20 years

111. Screening for Microalbuminuria Albumin excretion increased due to Strenuous exercise Oral Protein intake Urinary infection Fluid loading Pregnancy

112. Urinary Albumin Excretion Rates Normoalbuminuria < 30mg/day Microalbuminuria 30-300mg/day Overt Nephropathy > 300mg/day

113. Screening for Microalbuminuria Type 1: Yearly after 5 years of diagnosis Type 2: Annually from diagnosis

114. 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

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

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

117. Mechanisms for the Renoprotective Effect of ACE Inhibitors Inhibit non Heamodynamic effects of Angiotensin on various cell types Reduction in Cytokine and Growth factor synthesis e.g. TGF β Mesangium: Reduced Cell proliferation Hypertrophy Matrix Expansion

118. Mechanisms for the Renoprotective Effect of ACE Inhibitors Reduction in Oxidative Stress Inhibit macrophage activation, proliferation and migration

119. Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Glomerular sclerosis Hyperglycemia Genetic factors D metabolism of glom. cells Treatment of DM nephropathy: Glucose control from T. Hostetter

120. Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Glomerular sclerosis Hyperglycemia Genetic factors D metabolism of glom. cells Treatment of DM nephropathy: Hypertension control from T. Hostetter

121. 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

122. 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

123. Role of Aldosterone in the Pathogenesis of Diabetic Nephropathy

124. 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

125. 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

126. Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Glomerular sclerosis Hyperglycemia Genetic factors D metabolism of glom. cells Treatment of DM nephropathy: Effect of ACEIs and ARBs from T. Hostetter

127. 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

128. ACEi - or ARB-Based Regimens for Diabetic Nephropathy Do Not Go Far Enough!

129. 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

130. Secondary hyperparathyroidism Abnormalities in metabolism of calcium and phosphorus in patients with chronic kidney disease

131. 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

132. 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

133. Anaemia May occur when GFR < 50 % & almost always present when GFR < 30 % Correct deficiencies Iron, Folic acid, Vit B 12 , 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

134. Vaccinations Hepatitis B 20 mcg each deltoid IM 0, 1, 2, 6 months Check Anti HBS titre post vaccination after 3 rd dose Only 60 % seroconvert in ESRD Pneumococcal vaccine Influenza vaccine

135. 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

136. 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

137. Options of renal replacement Hemodialysis Peritoneal dialysis Renal transplantation

138. 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

139. 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

140. 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

141. 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.

142. 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

143. 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

144. 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.

145. 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)

146. 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

147. Treatment of DM nephropathy: Effect of statins from T. Hostetter Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Glomerular sclerosis Hyperglycemia ROS Genetic factors D metabolism of glom. cells

148. 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

149. 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

150. 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)

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

152. When ESRD sets in.. : 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

153. Glycemic Control means FPG= 90-130 mg/dl PPPG <180 mg/dl HbA1c <7.0% Self-monitoring of blood glucose (SMBG) Medical Nutrition Therapy Restrict dietary protein to RDA of 0.8 g/kg body weight / day BP control Maintain BP <130/80 mm/Hg Glycemic control is a must….

154. When ESRD sets in.. : 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.